Stem Cell Research,
Tracked in Real Time.

Qi Xing, Shiyuan Xie, Jiaqi Ma et al.

Gal Keshet, Nissim Benvenisty

Human pluripotent stem cells (hPSCs) can self-renew indefinitely and differentiate into all three embryonic germ layers. We previously defined the essentialome of hPSCs using a genome-wide CRISPR screen, but the functions of each gene remain obscure. Here, we used a pooled single-cell CRISPR screen to investigate pluripotent-specific essential transcription factors (TFs). We found that most TFs form a highly interconnected gene regulatory network (GRN) that governs key aspects of pluripotency, including self-renewal, differentiation, survival, and transposable element expression. Interestingly, we identify multiple TFs that act as lineage-specific gatekeepers, blocking exit from pluripotency, and others that inhibit pluripotency, potentially balancing self-renewal and differentiation responsiveness. Finally, perturbing the GRN in naive hPSCs revealed both conserved and state-specific regulatory roles relative to primed cells. Altogether, our analysis defines an extended GRN for human pluripotency, offering insights into early human development. These findings may inform strategies to improve hPSC-based disease models and regenerative therapies.

Namitha Thampi, Cristina Calvo, Virginia Rodríguez-Cortez et al.

Yao Lin, Shuai Yue, Ding Qiu et al.

Spyridoula Kazantzi, Philip Victor Reducha, Kristian A. Haanes

National Institutes of Health Clinical Center (CC)

This study will evaluate the long-term functional status, psychosocial adjustment and quality of life of patients with different types of diseases and conditions who have had an allogeneic (donor) stem cell transplant. Information from this study may help patients and families know better what they may expect long-term after transplant and will help health care workers improve services to aid in patients' recovery. People 18 years of age or older who have had an allogeneic stem cell transplant three or more years before the start of this study may be eligible to participate. Participants complete a series of questionnaires once a year for three years. The questionnaires take about 40 minutes to complete and include information on patient demographics, patients' physical, social, and emotional functioning, spiritual well being, pain, mental health, general health, fatigue, and other areas of health-related quality of life. The questionnaires are completed at home or during normally scheduled follow-up visits to the NIH. Status: COMPLETED Conditions: Long Term Psychological Affects on HSCT

Shanghai Children's Hospital

Hypospadias is one of the common congenital malformation disorders in male children, with a ratio of about 1 to 300 in newborn boys. Proximal hypospadias, due to the underdeveloped corpus spongiosum, has a high incidence of postoperative complications (e.g., urethral fistula, stricture, recurrence of penile curvature), exceeding 50%. Traditional surgeries focus on urethral tubularization but fail to restore the corpus spongiosum, leading to long-term micturition and sexual dysfunction. Recent studies have shown that stem cell exosomes promote angiogenesis and tissue repair through paracrine mechanisms. Urine-derived stem cells (USC) have the advantages of non-invasive acquisition and high proliferative capacity, and the investigator's previous study found that the USCs secreted exosomes (USC-Exos) promoted the regeneration of cavernous sinusoids in an animal model. In this study, the investigators applied autologous USC-Exos for the first time to pediatric hypospadias surgery to evaluate its clinical value in corpus spongiosum reconstruction. Phase: NA Status: COMPLETED Conditions: Hypospadias Interventions: Exsome; Placebo

Medical University of South Carolina

This is a single-center, nonrandomized, open-label dose-escalation study followed by dose-expansion of CD19- CD34t metabolically programmed CAR T-cell therapy in adult patients with relapsed or refractory CD19 B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B-cell Non Hodgkin Lymphoma; Chronic Lymphocytic Leukemia Interventions: Cyclophosphamide injection; Fludarabine Injection; CD19-CD34t metabolically programmed CAR transduced T-cells

Shengqiang Chen, Mingrui Luo, Sizhen Chen et al.

The inflammatory pathological microenvironment of osteoarthritis (OA) degrades the cell state and function of stem cell-derived grafts and presents a major obstacle to developing effective cell therapies. Here, we show that the viability and hyaline cartilage phenotype of bone marrow-derived mesenchymal stem cell (BMSC)-derived chondrocyte microspheroids (CMSs) can be efficiently preserved during spheroidization with persistent H2 supply and in an OA microenvironment. We therefore developed TiSi2 nanosheets (TSN) that hydrolytically generate a sustained (> 2 months) high dose of H2 and construct a H2-releasing hydrogel transplant (TSN/CMS-Gel) by encapsulating TSN and CMSs within a photo-crosslinking hydrogel (Gel). Transplantation of TSN/CMS-Gel achieves a strong survival of chondrocytes in a rodent OA model and promotes the rapid and efficient repair of sheep osteoarthritic critical-size cartilage defects, as well as the reversal of osteoarthritic progression within 6 months. The proposed strategy of locally sustaining H2-mediated preservation of transplanted chondrocytes in the pathological microenvironment opens new opportunities to enhance cell transplantation outcomes.

Shuyue Xu, Jingwen Xu, Qiqi Yang et al.

Tumors are increasingly recognized as a consequence of systemic immune dysregulation, while current therapies merely focus on direct tumor killing or local immune activation, overlooking the systemic immune landscape that enables tumorigenesis and metastasis. Targeting distal immune organs, such as the bone marrow (BM), without perturbing tumors remains challenging. Here, we develop a BM-targeted and tumor-evasive cell vector that restricts immunomodulation to the BM niche, enabling systemic immune reprogramming through niche-derived signaling. This mesenchymal stem cell (MSC)-based vector overexpresses Golgi apparatus protein 1 (MSCglg1) to mimic BM affinity signals. In a myelosuppression model, MSCglg1 delivers CDK4/6 inhibitors (CDK4/6i) to protect hematopoietic stem and progenitor cells (HSPCs) from chemotherapy toxicity while preserving antitumor efficacy. In a subcutaneous tumor model, MSCglg1 delivers interleukin-7 (IL-7), restoring immune competence without promoting tumor proliferation. This strategy establishes a versatile framework for targeted immunomodulation to treat cancer as a systemic immune disease.

Marc Vila Cuenca, Theano Tsikari, Minne N Cerfontaine et al.

cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary brain small vessel disease caused by pathogenic variants in the NOTCH3 gene, leading to NOTCH3 protein accumulation and degeneration of vascular smooth muscle cells (VSMCs). Here, we developed a CADASIL 3D Vessel-on-Chip model using either primary brain VSMCs or human induced pluripotent stem cell (hiPSC)-derived VSMCs from CADASIL patients and isogenic controls. In 3D co-culture with hiPSC-derived endothelial cells, both primary and hiPSC-derived CADASIL VSMCs exhibited disease-relevant morphological abnormalities, increased NOTCH3 and contractile protein levels, and altered intracellular Ca2+ dynamics that were not observed under conventional 2D culture. PDGFRβ, a downstream NOTCH3 target, was upregulated and correlated with NOTCH3 protein levels in both 3D models and CADASIL patient brain tissue. Pharmacological inhibition of NOTCH3 cleavage reduced NOTCH3 protein levels and rescued CADASIL VSMC phenotypic abnormalities. In conclusion, this 3D Vessel-on-Chip model robustly shows CADASIL pathology-relevant readouts and provides a platform for mechanistic studies and therapeutic testing.

Dayoung Kim, Takayuki Kondo, Haruhisa Inoue

Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss. Microglia, the brain's resident macrophages, are key contributors to disease pathogenesis, with many genetic risk variants enriched in microglia-specific genes. While rodent models have provided valuable insights, human induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC) technologies now enable the generation of human microglia-like cells, offering a physiologically relevant platform to study human microglial biology. This review discusses the developmental origins and functions of microglia, current differentiation approaches, and how these models help elucidate disease-relevant phenotypes and molecular mechanisms in neurodegeneration.

Roger A Barker, Agnete Kirkeby

Youyi Tai, Lu Jin, Thamidul Islam Tonmoy et al.

Neural crest stem cells (NCSCs), capable of differentiating into neurons and Schwann cells, are essential for peripheral nerve regeneration. This study investigates the role of endogenous NCSC-like cells in mechano-electrical stimulation (MES)-enhanced peripheral nerve repair. In a critical-sized nerve injury model, MES leads to complete nerve reconnection, accompanied by a significant increase in NCSC-like cells at the injury sites. In vitro, MES promotes the simultaneous differentiation of NCSC-like cells into neurons and Schwann cells, with elevated neuregulin 1 (NRG1) expression, a key factor in Schwann cell development. Mechanistically, MES activates BMP/Smad signaling, driving neuronal differentiation and subsequent NRG1 secretion, which in turn promotes Schwann cell maturation through the ErBB/NFAT pathway. These findings demonstrate that MES enhances peripheral nerve regeneration by activating and directing stem cell differentiation, supporting a novel therapeutic approach that utilizes physical stimulation for stem cell modulation for nerve repair.

Karen Bellec, Lynsey R Carroll, Kathryn A F Pennel et al.

The PIWI-interacting RNA (piRNA) biosynthesis pathway is best studied for its role in suppressing Drosophila germline transposable elements. Piwi, the founding member of the pathway, is involved in adult intestinal stem cell (ISC) homeostasis. Whether a broader role of the PIWI pathway exists in the intestine remains unknown. Here, we characterize a role of the PIWI family protein Aubergine (Aub) in ISCs. While dispensable for basal ISC self-renewal, upregulation of Aub by damage-induced reactive oxygen species drives regenerative ISC proliferation through increased protein synthesis, including translation of ISC factors Myc and Sox21a. Unexpectedly, such roles of Aub in ISCs appear uncoupled from its piRNA regulatory function. Additionally, Aub and mammalian PIWIL1 mediate tumorigenic intestinal growth in Drosophila and human organoids, respectively. Our results reveal regulated protein translation as a fundamental aspect of regenerative ISC function and discover a central role of Aub in such process.

Sonja Bendig, Alina M Hartmann, Wiebke Wessels et al.

Large scale sequencing efforts have defined up to 27 diagnostic entities in B-ALL, leaving few samples without subtype assignment. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection and holds the potential to identify novel B-ALL subtypes. By analyzing an aggregated set of 4,857 B-ALL patients from three cohorts, we identified a novel group of twenty cases (age 18-66 years, median: 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n=17/20), KRAS p.A146T/V/P mutations (n=17/20 vs. n=86/4,857; p<0.001) and distinct DNA-methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 ('FOXF1/FENDRR') as well as JAK/STAT and RAS signaling signatures. A gene expression machine learning classifier identified FOXF1/FENDRR cases in two independent cohorts with high accuracy. Patients treated according to GMALL/GRAALL protocols showed very poor chemotherapy response with n=8/13 having induction failure or MRD &#x2265;10-3 and n=8/12 remaining MRD positive after 1st consolidation / salvage. MRD-stratified intensification including blinatumomab (n=10) and/or allogenic stem cell transplantation (n=12) resulted in ongoing molecular remission in 13/16 cases. FOXF1/FENDRR patients represent a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.

Anne Marchalot, Malin Ljunggren, Christopher Stamper et al.

Abstract Peritoneal metastases (PM) occur in 10% of patients with colorectal cancer (CRC) and are linked to poor outcomes. Although dysregulated innate lymphoid cells (ILC) have been described in CRC, their function in CRC-PM remains unclear. Here, we analyze tumor samples from CRC and CRC-PM patients using single-cell RNA sequencing (11 patients), flow cytometry (8 patients) and differentiation assays (24 patients). Healthy colon, primary CRC and CRC-PM tumors are infiltrated by heterogeneous populations of ILC3, ILC2, ILC1, tissue resident (tr)NK cells and conventional (c)NK cells. Compared to healthy colons, primary CRC and CRC-PM tumors are depleted of ILC3 but enriched for ILC1, trNK cells and cNK cells. CRC and CRC-PM tumors harbor two immature ILC populations, early NK and naïve (n)ILC, with nILCs being transcriptionally skewed toward ILC1 and trNK cells. Indeed, co-culture of isolated nILCs with OP9-DL1 cells induces intratumoral nILC differentiation into ILC1/trNK-like cells. These findings help understand the immune pathogenesis of CRC and CRC-PM and provide insights for future ILC1 and NK cell-based therapies.

Binbin Ma, Guanghui Yang, Jonathan Yao et al.

The olfactory epithelium possesses an adult stem cell population, the horizontal basal cells (HBCs), to permit lifelong tissue regeneration. Here, we show that HBCs exhibit asymmetric inheritance of histone H4 but not H2A-H2B during olfactory epithelium regeneration in mice. Primary HBC cultures further revealed asymmetric histone inheritance for H3 and H3.3. Upon mitotic exit, asymmetric histone inheritance correlates with asynchronous transcription re-initiation and differential enrichment of p63, a key transcription factor for HBC cell fate. Disruption of asymmetric histone inheritance abolishes these asymmetric cellular features and attenuates olfactory epithelium regeneration and smell behavior recovery. Single-cell RNA sequencing of paired HBC daughters in culture further supports asymmetric multilineage cell fate priming. Together, these findings reveal asymmetric histone inheritance in a mammalian adult stem cell lineage and highlight its biological significance in neural tissue regeneration and animal behavior.

Xiaoyu Qiu, Zehua Lin, Yuechen Sun et al.

Moonlight Bio, Inc

This is a first-in-human (FIH), open-label, Phase 1 study designed to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of ML261, an autologous potency enhanced anti-DLL3 CAR T cell therapy, in participants with R/R SCLC or select NECs Phase: PHASE1 Status: NOT_YET_RECRUITING Conditions: Small Cell Lung Cancer (SCLC ); Extrapulmonary Neuroendocrine Carcinoma (EP-NEC); Gastroenteropancreatic NEC (GEP NEC); Neuroendocrine Prostate Cancer (NEPC) Interventions: ML261

St. Jude Children's Research Hospital

This study is being done to learn more about the short-term and long-term side effects of CAR-T cell therapy. Specifically, researchers want to know how often patients get infections, have delays in recovering blood cell counts and/or have damage to the nervous system. Status: RECRUITING Conditions: B-ALL; Hematologic Malignancy; Solid Tumor

Jaqueline Cardoso do Prado Bayma, Jonathan Edwin Baracho Trindade Hill, Ana Beatriz Molina et al.

Canine distemper has a high mortality rate in the acute phase, and survivors typically suffer irreversible, progressive neurological sequelae, due to demyelinating leukoencephalitis, under current treatment standards. Mesenchymal stromal cells (MSCs) are found in the adult organism and represent a promising alternative for treating central nervous system disorders by secreting trophic and immunomodulatory factors that reduce inflammation, protect neurons, and promote regeneration. The therapeutic action of MSCs is largely mediated by the secretion of trophic and immunomodulatory factors, including anti-inflammatory cytokines, anti-apoptotic proteins, and neurotrophins.

Surya Nagaraja, Lety Ojeda-Miron, Ruochi Zhang et al.

Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear1,2. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100&#x2009;days. Here we find that memory of colitis is characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. This approach reveals that memory of colitis is propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others. Finally, we show that colitis primes stem cells for increased expression of an AP-1-regulated gene program following oncogenic mutation that accelerates tumour growth, a phenotype dependent on AP-1 activity. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential diagnostic and therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.

Xingjie Ren, Lina Zheng, Yuxi Liu et al.

Precise transcriptional regulation is critical for cellular function and development, yet the mechanism of this process remains poorly understood for many genes. To gain a deeper understanding of the regulation of neuropsychiatric disease risk genes, we identify a total of 39 functional enhancers for four dosage-sensitive genes, APP, FMR1, MECP2, and SIN3A, using CRISPR tiling deletion screening in human induced pluripotent stem cell (iPSC)-induced excitatory neurons. More importantly, we discover that allelic enhancer deletions at SIN3A could be compensated by increased transcriptional activities from the other intact allele. Such allelic compensation effects (ACE) on transcription are stably maintained during differentiation and, once established, cannot be reversed by ectopic SIN3A expression. Further, ACE at SIN3A occurs through dosage sensing by the promoter. Together, our findings unravel a regulatory compensation mechanism that ensures stable and precise transcriptional output for SIN3A, and potentially other dosage-sensitive genes.

Xiaosu Li, Wenwen Lu, Marisa Connell et al.

Termination of Notch signaling is essential for the specification of differentiating progeny during asymmetric stem cell division. Using Drosophila type II neural stem cells as a model, here we report that, in addition to asymmetric segregation of Numb, fate specification of differentiating progeny also requires the expression of the Notch target E(Spl)m&#x3b3; in the stem cell to be kept at low levels by the SPEN family proteins, Split End (Spen) and Spenito (Nito). Loss of Spen or Nito leads to a drastic increase in E(Spl)m&#x3b3; expression in the stem cell and dedifferentiation of the progeny. We demonstrate that Spen and Nito repress E(Spl)m&#x3b3; expression by binding to two identical motifs in the 5' untranslated region to repress the translation. The low E(Spl)m&#x3b3; expression in the stem cell ensures its rapid removal from the progeny. Together, our work uncovers a post-transcriptional mechanism regulating Notch signaling during asymmetric stem cell division.

Sari Ansch&#xfc;tz, Hannah M&#xfc;ller, Andrea Schubert et al.

Controlled signaling activity is vital for normal tissue homeostasis and oncogenic signaling activation facilitates tumorigenesis. Here, we combine single-cell transcriptomics with in-depth genetic and imaging analysis to investigate the role of the EGFR-Ras and Hedgehog signaling pathways in homeostasis of the Drosophila follicle stem cell lineage. We find that Hedgehog signaling simultaneously promotes an undifferentiated state and induces differentiation via activation of the epithelial-mesenchymal-transition associated transcription factor Zfh1. Overactivation of Hedgehog signaling generates a mixed transcriptional state comparable to partial epithelial-mesenchymal-transition. EGFR-Ras overactivation induces cell cycle defects by activating the transcription factors Pointed and E2f1 and impedes differentiation. Overactivation of both pathways blocks differentiation and induces tumor-like growth where follicle cells exhibit a loss of tissue architecture, sustained proliferation and a reduced lifespan of the host. These findings provide new insight into how signaling pathways converge at the transcriptional level to prevent malignant cell behavior.

Jeffrey S. Schweitzer, MD, PhD

The goal of this clinical trial is to assess the safety and tolerability of the surgical transplantation of dopaminergic progenitor cells into the brains of participants with Parkinson's disease. The transplanted dopaminergic cells will be derived from the participant's own skin cells. Phase: PHASE1 Status: RECRUITING Conditions: Parkinson Disease Interventions: autologous dopaminergic cell implantation

Mohammad Samie, Toufan Parman, Mihika Jalan et al.

Peripheral neuropathies are estimated to affect several million patients in the US, with no long-lasting therapy currently available. In humans, the Nav1.7 sodium channel, encoded by the scn9a gene, is involved in a spectrum of inherited neuropathies and has emerged as a promising target for analgesic drug development. The development of a selective Nav1.7 inhibitor has been challenging, in part because of structural similarities with other Nav channels. Here, we present preclinical studies for a genomic medicine approach using engineered zinc finger repressors (ZFRs) specifically targeting the human/nonhuman primate (NHP) scn9a gene. Adeno-associated virus (AAV)-mediated delivery of ZFRs in human induced pluripotent stem cell (iPSC)-derived neurons resulted in the reduction of scn9a with no detectable off-target activity. In the spared nerve injury (SNI) neuropathic pain mouse model, AAV-ZFR administration resulted in &#x2264;70% repression of scn9a in mouse dorsal root ganglia (DRGs) and was associated with reduction in pain hypersensitivity. AAV9-mediated intrathecal-lumbar (IT-lumbar) delivery of ZFRs in NHPs demonstrated repression of scn9a in bulk DRG tissue and single-cell levels in nociceptors 1 month after treatment. A lead AAV9-ZFR investigational product, ST-503, was developed and further evaluated in a 6-month study in NHPs. ST-503 administration by IT-lumbar infusion resulted in 50% repression of scn9a in bulk DRG tissue at 6 months without findings of dose-limiting toxicity or impact on neurological and cardiac safety pharmacology. Together, our results support further development of an AAV-delivered ZFR as a potential therapy for patients with peripheral neuropathies.

Kehua Zhang, Tao Na, Chuncui Jia et al.

Human induced pluripotent stem cells (hiPSCs) may acquire genomic alterations during reprogramming and culture, which poses significant risks for clinical applications. Current detection methods, such as karyotyping analysis, often fail to identify critical submicroscopic variations. This highlights an urgent need for comprehensive genomic surveillance strategies.

Xue Han, Minyi Zhao, Kexin Wang et al.

The role of inflammation-induced myeloid-biased hematopoiesis in driving resistance to immune checkpoint blockade (ICB) is recognized, yet the intricate mechanisms through which tumors orchestrate it are not fully defined.

Tasnim Azad, Kimsor Hong, Feifeng Wu et al.

Clinical responses to mesenchymal stromal cell (MSC) therapies remain variable because MSCs are often treated as uniform biologics despite donor-programmed differences. Evidence indicates that developmental maturity (fetal vs. adult) and biological sex (female vs. male) bias the MSC secretome and downstream signalling (NF-&#x3ba;B, PI3K/AKT-ERK, TGF-&#x3b2;/Smad, Wnt/&#x3b2;-catenin), potentially shaping anti-inflammatory, angiogenic, anti-fibrotic, and regenerative functions.

Masahiro Kuragano, Naoki Nishishita, Koki Araya et al.

In early drug discovery, in vitro screening is frequently used, but selected candidates often fail in vivo. Induced pluripotent stem cell (iPSC)-based disease models offer improved physiological relevance; however, the high costs of media and differentiation procedures limit large-scale testing. Here, we develop a high-throughput conditioned-media-based screening system-the High-throughput screening technology for Aggregation Inhibitors of Diseased cell-derived Aggregative Proteins (HaiDap) system-to identify inhibitors of aggregation induced by iPSC-secreted amyloid &#x3b2; (A&#x3b2;). Using conditioned media derived from differentiated iPSCs of a male Alzheimer's disease patient, we screen extracts from 22 edible plants. Whereas PBS-based assays showed 40.9% (9/22) apparent selectivity, the HaiDap system demonstrates higher specificity (13.6%; 3/22). All three identified extracts (O. aristatus, S. aromaticum, and G. yesoense) significantly delay A&#x3b2; aggregation on neuronal surfaces in an iPSC-based assay. These findings suggest that the HaiDap system enables efficient, accurate, and low-cost screening of amyloid aggregation inhibitors.

Guangzhou FineImmune Biotechnology Co., LTD.

This study was a phase I safety and tolerability clinical trial conducted in a single-center, open-label, 3+3 design with dose escalation. Phase: PHASE1 Status: RECRUITING Conditions: Advanced Hepatocellular Carcinoma (HCC); GPC3 Positive Hepatocellular Carcinoma Interventions: Super CAR-T

Canadian Cancer Trials Group

The purpose of this study is to evaluate the effects of adding two oral medications (sonrotoclax plus zanubrutinib) to standard of care chimeric antigen receptor (CAR-T) cell therapy in participants with mantle cell lymphoma. Phase: PHASE2 Status: NOT_YET_RECRUITING Conditions: Mantle Cell Lymphoma Interventions: Zanubrutinib; Sonrotoclax; CAR-T Cell Therapy

Memorial Sloan Kettering Cancer Center

The researchers are doing this study to find out whether PK-targeted fludarabine is an effective Lymphodepletion (LD) chemotherapy approach for people with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) who will receive tisagenlecleucel CAR T-cell therapy. The researchers will compare PK-targeted fludarabine dosing with standard fludarabine dosing to see which treatment approach is more effective. The researchers will also look at whether PK-targeted fludarabine dosing is feasible (practical), the side effects of the study treatment, and how the study treatment affects people's quality of life. The researchers will measure quality of life by having participants complete questionnaires. Phase: PHASE3 Status: RECRUITING Conditions: B-cell Acute Lymphoblastic Leukemia Interventions: Fludarabine; Cyclophosphamide; Fludarabine; CAR-T

Michelle Lohbihler, Amos A Lim, St&#xe9;phane Mass&#xe9; et al.

The atrioventricular node (AVN) ensures synchronized heart contractions by establishing the electrical connection between the atria and ventricles. Dysfunction of the pacemaker cells of the AVN leads to atrioventricular block (AV block), a life-threatening condition managed with electronic pacemakers (EPMs). EPMs have drawbacks that could potentially be overcome by a human pluripotent stem cell (hPSC)-derived biological conduction bridge (BioCB). Recent studies demonstrated the differentiation of AVN-like cells from hPSCs, but their conduction properties upon engraftment in vivo remain unexplored. Here, we report the generation of AVN-like pacemaker cells (AVNLPCs) from hPSCs using Wnt and BMP signaling modulation. These AVNLPCs transcriptionally resemble fetal AVN pacemaker cells, exhibit pacemaker action potentials, and display unique AVN-like conduction properties. Notably, when transplanted into the guinea pig heart, AVNLPCs replicate the functional properties of the AVN. Our study highlights the potential of an AVNLPC-based BioCB as a novel cell therapy to improve treatment for patients with AV block.

Ashley N Kamimae-Lanning, Jill M Brown, Matthias G&#xfc;nther et al.

DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial for embryonic HSC emergence and throughout life. Despite severe deficiencies in HSCs, these mice produced blood for many months. To determine what enables this, we employed an unbiased method for detecting clones, which exploits somatic variant data. This revealed initial polyclonal hematopoiesis that diminishes to monoclonal hematopoiesis, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to the last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.

IRCCS Azienda Ospedaliero-Universitaria di Bologna

This observational study evaluates growth and endocrine outcomes in pediatric oncology patients who underwent prepubertal HSCT compared to those who did not. The study focuses on final height, pubertal growth spurt, and sex hormone production, with data collected retrospectively and prospectively through standard clinical follow-up. Status: NOT_YET_RECRUITING Conditions: Hematopoietic Stem Cells Transplantation; Pediatrics

Minkyu Lee, Xin Wang, Qihua Ye et al.

Tissue-resident stem cells play an essential role in repairing barrier tissues subjected to frequent insults. However, the local cues that coordinate successful barrier repair or lead to tissue remodeling are largely unknown. Here we use murine models of airway injury, fate mapping, and null strains to identify a role for rare tuft epithelial cells in signaling to submucosal stem cells through the generation of cysteinyl leukotrienes (CysLTs) and activation of the CysLT receptor OXGR1. This results in mobilization of SOX9+ submucosal gland progenitors, aberrant repair of the surface airway epithelium, and durable features of airway remodeling including submucosal gland hyperplasia and collagen deposition. Remarkably, selective deletion of SOX9 from the airway stem compartment allows epithelial restoration and prevents tissue remodeling. These findings demonstrate a tuft cell- OXGR1- and SOX9- circuit that remodels the airway after injury and is detected in the human sinus mucosa.

Miguel F Tenreiro, Alysson R Muotri

Understanding the neurodevelopmental biology of the human brain remains a major challenge, primarily due to the lack of model systems that accurately reflect the evolutionary innovations underlying human-specific cell-type diversification, cortical expansion, and higher-order cognition. Cerebral organoids have emerged as powerful stem-cell-derived systems that offer unique opportunities to investigate these processes. Here, we discuss the cellular and molecular features that define human telencephalic development, evaluate how faithfully organoid models mirror in vivo developmental programs, and explore their potential for modeling neurodevelopmental disorders and for therapeutic discovery. We also critically assess the current limitations of cerebral organoids and highlight emerging strategies to enhance their fidelity and translational utility.

The First Affiliated Hospital of Soochow University

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, relapse after CAR-T has been a major issue. Multi-antigen CAR T and combination with other regimens may reduce the relapse rate. We conduct pre-auto-HSCT immunotherapy to achieve MRD negative remission, then perform auto-HSCT followed by CD22/CD19 CAR-T "sandwich " strategy in AYA and adult patients with B-ALL. The main Purpose of this study was to observe the safety and efficacy of this new strategy. Phase: PHASE2 Status: NOT_YET_RECRUITING Conditions: Acute Lymphobkastic Leukemia Interventions: Sandwich stratergy

Tcelltech Inc.

This is a phase I, open-Label, single/multiple dose, dose-escalation study to evaluate the safety, tolerability and antitumor activity of anti-B7-H3 CAR-T cell injection (TX103) in subjects with recurrent or progressive Grade 4 Glioma.The study also plan to explore the Maximum Tolerated Dose (MTD) and determine the Recommended Phase II Dose (RP2D) of the CAR-T cell therapy. Phase: PHASE1 Status: RECRUITING Conditions: High-grade Glioma; WHO Grade Ⅳ Glioma Interventions: Anti-B7-H3 Chimeric Antigen Receptor T-Cell (CAR-T Cell) Injection/TX103

Yi Sun, Juan Yu, Yang Shi et al.

Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid deterioration of liver function, resulting in high mortality and posing a substantial global health burden. Human embryonic stem cells (hESCs) possess unlimited self-renewal capacity and pluripotent differentiation potential. Transplantation of hESC-derived hepatocyte-like cells (HPLCs) represents a promising therapeutic strategy for ALF.

Li Chunxiao, Fan Junsheng, Chen Xuerong et al.

Tuberculosis (TB) remains a major global public health challenge, with drug-resistant tuberculosis (DR-TB) presenting a serious threat to TB management. Conventional treatment faces challenges such as significant drug toxicity, frequent emergence of drug resistance, and compromised host immune microenvironment. These limitations, particularly in DR-TB cases, often lead to poor treatment outcomes and heightened recurrence rates, underscoring the need for complementary strategies. Cell-based host-directed therapy (HDT) emerges as a novel therapeutic strategy that may complement conventional drugs by directly modulating pathological immune responses and facilitating the repair of damaged tissue. This narrative review synthesizes preclinical and clinical data on cell therapy for TB. We focus on two distinct strategic approaches: (1)&#xa0;mesenchymal stem cell (MSC)-based therapies, which primarily exert immunomodulatory and tissue-repair functions, and (2)&#xa0;T cell-based adoptive cell therapies (ACTs), which are designed to enhance antimicrobial immunity directly. Current evidence, while promising, predominantly remains in the early exploratory stages or lacks robust evidence-based support. To facilitate successful translation, future research should focus on standardizing cell products, conducting comprehensive safety assessments and implementing more rigorous clinical trials. This review critically assesses the therapeutic potential and translational challenges of cell therapy for TB.

National Cancer Institute (NCI)

This phase II trial tests the safety and side effects of glofitamab and obinutuzumab and how well they work in treating patients with mantle cell lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory) after receiving CD19-directed chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a form of immunotherapy where the immune system cell, T-cell, is changed to attack cancer cells. Glofitamab is a bispecific antibody that can bind to two different antigens at the same time. Glofitamab binds to CD3, a protein found on T cells (a type of white blood cell), and CD20 a protein found on B cells (another type of white blood cell) and some lymphoma cells. This may help the immune system kill cancer cells. Obinutuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Giving glofitamab and obinutuzumab may be safe, tolerable, and/or effective in treating patients with relapsed or refractory mantle cell lymphoma after receiving CD19-directed CAR T-cell therapy. Phase: PHASE2 Status: RECRUITING Conditions: Recurrent Mantle Cell Lymphoma; Refractory Mantle Cell Lymphoma Interventions: Biospecimen Collection; Computed Tomography; Glofitamab; Obinutuzumab; Positron Emission Tomography

Sulaiman Mohammed Alnasser

Circadian rhythms are endogenous, transcription-translation feedback loops that align cellular activities with the 24-h light-dark cycle. Stem-cell populations across tissues exhibit circadian oscillations that influence their self-renewal, proliferation, and differentiation. Key developmental pathways (Wnt/&#x3b2;-catenin, Notch, and Hedgehog) are increasingly recognized as both regulators and targets of circadian machinery.

Konstantina Chanoumidou, Ioanna Zota, Maria Anna Papadopoulou et al.

Hyperglycemia, a hallmark of diabetes mellitus, is a metabolic condition that highly affects the nervous system. While evidence from epidemiological and animal studies links diabetes to dopaminergic dysfunction and an increased risk of Parkinson's disease, the underlying mechanisms remain unclear. Here, we examined the effects of high glucose on human iPSC-derived dopaminergic neurons and glial cells to better understand the pathogenic alterations that lead to neurotoxicity. Previous implication of neurotrophins in the neurological manifestations of diabetes prompted us to focus on the role of p75NTR neurotrophin receptor (p75NTR) in dopaminergic neurodegeneration under hyperglycemic conditions.

Jay English, Danny McSweeney, Jinghui Geng et al.

Copy-number deletions in the 2p16.3/NRXN1 locus confer genetic risk for autism spectrum disorder (ASD) and schizophrenia (SCZ). Prior studies showed that heterozygous NRXN1 deletions reduce excitatory synaptic transmission in human induced pluripotent stem cell (iPSC)-derived cortical induced neurons, a phenotype also observed in SCZ patient lines carrying NRXN1 deletions. However, it remains unknown whether similar synaptic deficits exist in ASD patients with NRXN1 deletions. Clarifying this is important for determining whether NRXN1-deletion carriers should be approached uniformly or with consideration of disorder background, genetic modifiers, and deletion breakpoints. Here, we show that ASD-associated NRXN1 deletions alter cortical synaptic function in distinct ways. ASD deletions selectively enhance excitatory synaptic signaling without affecting inhibitory synapses, whereas SCZ deletions reduce both. At the network level, ASD deletions generate irregular firing patterns and impair homeostatic synaptic plasticity. Our study uncovers disorder-dependent synaptic mechanisms linked to NRXN1 deletions, providing a foundation for targeted therapeutic strategies for NRXN1-related disorders.

Haochen Tu, Aoi Hosaka, Genki Hichiwa et al.

Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but their clinical utility is limited by replicative senescence. Strategies that reverse aging while maintaining MSC identity are urgently needed.

Louison Descampe, Benjamin Dassy, Fadi Charara et al.

Cell plasticity supports tissue regeneration but can also drive metaplasia, increasing cancer risk in many tissues, including the esophagus. Understanding how esophageal progenitor plasticity is regulated is therefore essential. We previously identified Sox9 as a key regulator of this plasticity downstream of Hedgehog signaling, which is reactivated by chronic acid reflux. Here, we show that Hedgehog regulates Sox9 indirectly through epithelial-stromal communication and directly via cell-autonomous mechanisms. Activation of TGF-&#x3b2; and BMP pathways synergistically induces Sox9 and promotes a transcriptomic state resembling squamo-columnar junction progenitors predisposed to metaplasia. We also uncover an epithelial cell-intrinsic mechanism whereby Cox-2 modulates this plasticity. Cox-2 inhibitors suppress Hedgehog-induced Sox9 expression through direct effects on epithelial cells in both mouse and human models. Together, these findings provide proof of concept that pharmacological modulation of epithelial plasticity may offer new strategies for regenerative medicine and for the prevention or treatment of metaplasia.

Fang Yuan, Ye Sing Tan, Haofei Wang et al.

We identified a new progeroid syndrome with severe neuropathy and intellectual deficits but its underlying cellular and molecular mechanism is unknown. Exome sequencing revealed a homozygous mutation in the IVNS1ABP gene, which encodes IVNS1ABP, an influenza virus non-structural protein-1 binding protein. To investigate disease mechanisms, we generated isogenic induced pluripotent stem cells (iPSCs) from patient fibroblasts and differentiated them into neural progenitor cells (NPCs). Mutant IVNS1ABP fibroblasts, iPSCs, and NPCs exhibited defective cytokinesis, increased DNA damage, and premature cellular senescence. Consistent with these findings, cerebral organoids showed early differentiation of NPCs into neurons. Molecular profiling as well as biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin / actin-associated proteins and dysregulated actin dynamics during cytokinesis. Taken together, we propose that mutant IVNS1ABP dysregulates actin polymerization and organization which is at least partly responsible for the cellular senescence phenotypes in this progeroid neuropathy.

Haipeng He, Jiamin Huang, Jingyi Yuan et al.

Alice H&#xe4;gg, Rachel Wood, Ayako L Mochizuki et al.

Despite rapid clinical translation, induced pluripotent stem cell (iPSC)-derived therapies face limited global adoption. Harmonized quality control (QC) remains absent, with even fundamental parameters evaluated inconsistently across laboratories. To address this, we conducted two international Quality Assessment Rounds (QARs): QAR 2019 (18 sites, 11 countries) and QAR 2023 (23 sites, 12 countries), evaluating flow cytometry-based assessment of the undifferentiated state and qPCR-based genomic integrity testing. QAR 2019 showed high consistency in genomic integrity testing, while uncovering substantial variability in flow cytometry, prompting QAR 2023 to introduce standardized workflows. These improvements enabled systematic, cross-site evaluation of marker performance across cell states, identifying OCT3/4, TRA-1-60, and SSEA5 as consistently robust pluripotency-associated markers. This global benchmarking effort provides the first empirical multi-site evidence for reproducible iPSC QC and marker-level reliability. Together, these findings establish a foundation for harmonized QC supporting interoperable iPSC banks, regulatory alignment, and scalable manufacturing of globally accessible regenerative therapies.

Jesse Weidema, Hanna Lammertse, Martine de Vries et al.

Human induced pluripotent stem cell (hiPSC) models inherit donor-specific variation, affecting experimental outcomes and generalizability. While diversity is widely discussed in biomedical research and extensively theorized in genomics, comparable guidance remains limited in hiPSC research. In response, this paper extends genomics frameworks to provide stem cell-specific recommendations for describing and reporting diversity and introduces a decision framework based on four criteria (experimental purpose, biological plausibility, platform readiness, and statistical power) to determine when and how diversity should be incorporated in hiPSC-based research. The overall goal is to establish a shared basis for transparent and reproducible diversity-related design and reporting.

National Institute on Aging (NIA)

Background: Bone marrow is the soft material found inside most large bones of the body. Bone marrow produces red blood cells, white blood cells, and platelets that are released into the blood stream. Inside the marrow, these cells start off as young, immature cells called progenitor cells. Researchers want to study these cells in healthy people. Objective: To understand how progenitor cells change with age. Eligibility: Healthy people ages 18 and older Design: Participants will be screened with a questionnaire, a physical exam, and blood tests. Participants will have a bone marrow aspirate. They will be asked to lie on their stomach or side. A local anesthetic will be injected with a small needle under the skin at the site. A needle will then be placed through the skin and into the hip bone. A small amount of the liquid part of the bone marrow will be taken up into the needle. After the needle is removed, a pressure bandage will be placed on the site. Participants will be asked to become a repeat volunteer and have a bone marrow aspirate sample collected once every other year. They will have a physical exam and blood tests before each collection. The cells from the collection will be used for genetic testing and research. Participants will be in the study for as long as they remain healthy and willing to participate. ... Status: RECRUITING Conditions: Normal Aging

National Institute of Allergy and Infectious Diseases (NIAID)

The research goal of this study is to obtain CD34+ hematopoietic stem cells (HSC) from peripheral blood and/or bone marrow, and Mononuclear Cells (lymphocytes and monocytes), and granulocytes (grans) from peripheral blood that will be used in the laboratory and/or in the clinic to develop new cell therapies for patients with inherited or acquired disorders of immunity or blood cells. Development of novel cellular therapies requires access to HSC, Mononuclear Cells and/or granulocytes as the essential starting materials for the pre-clinical laboratory development of gene therapies and other engineered cell products. HSC or blood cells from healthy adult volunteers serve both as necessary experimental controls and also as surrogates for patient cells for clinical scale-up development. HSC or blood cells from patients serve both as the necessary experimental substrate for novel gene therapy and cellular engineering development for specific disorders and as pre-clinical scale up of cellular therapies. Collection of cells from adult patients collected in the NIH Department of Transfusion Medicine (DTM) under conditions conforming to accepted blood banking clinical practice may also be used directly in or cryopreserved for future use in other NIH protocols that have all required regulatory approvals allowing such use. In summary, the research goal of this protocol is the collection of HSC or blood cells that may be used for both laboratory research and/or for clinical treatment in other approved protocols. Status: RECRUITING Conditions: Granuloma; Granulomatous Disease, Chronic; Leukocyte Disease; Genetic Disease, X-Linked; Genetic Disease, Inborn

National Institute of Allergy and Infectious Diseases (NIAID)

Idiopathic CD4 lymphocytopenia (ICL) is a rare syndrome defined by consistently low CD4 T cell counts (\<300/mm3) without evidence of HIV infection or other known immunodeficiency. Patients with ICL are at risk for opportunistic infections typically associated with HIV/AIDS such as disseminated cryptococcal infection and severe human papillomavirus-related dysplasia. More than 20 years since the description of ICL, its etiology, pathogenesis, and management remain unclear. In this study we propose to administer the combination of granulocyte colony stimulating factor (G-CSF) and plerixafor to ICL patients and healthy volunteers with the objective of harvesting mobilized CD34+ hematopoietic progenitor cells (HPCs) by apheresis for transfer into immunocompromised mice and for study with in vitro assays. The mice studies would serve to investigate thymic development, survival, and trafficking of the mobilized human cells within murine lymphoid and non-lymphoid organs. HPCs are used for various therapies and there is an increasing use of agents that stimulate the bone marrow to produce progenitor cells and move them into the bloodstream where they may be harvested by apheresis. Not all patients respond to GCSF with vigorous HPC mobilization. The binding of chemokine receptor CXCR4 to stromal cell derived factor (SDF-1 or CXCL12) is an important interaction between a hematopoietic progenitor cell and its marrow environment. Plerixafor is a CXCR4 inhibitor which blocks binding to SDF-1 resulting in the release of hematopoietic progenitor cells (CD34+) into peripheral circulation. In pharmacodynamic studies of plerixafor in conjunction with G-CSF compared to G-CSF and placebo, a two-fold increase in CD34+ cell count was observed. Due to the important role CXCR4 plays in immune cell trafficking and its potential role in the pathogenesis of ICL, we propose as a secondary objective to assess peripheral CD4 T cell and CD34+ hematopoietic progenitor cell numbers and functions in ICL patients compared to controls following G-CSF and plerixafor administration. Study participants will be screened within 12 weeks prior to the study period. Eligible participants will receive G-CSF for 5 days with hospitalization on Day 4 for plerixafor injection followed by apheresis on Day 5. Participants will return for examinations and blood draws on Days 8 and 12. ... Phase: PHASE2 Status: RECRUITING Conditions: Idiopathic CD4-Positive; T-Lymphocytopenia Interventions: Filgrastim; Plerixafor

Murdoch Childrens Research Institute

This randomised controlled trial will determine the non-inferiority of stopping empiric antibiotics prior to absolute neutrophil count (ANC) recovery (Early Stopping) versus stopping antibiotics upon ANC recovery (Standard of Care/ Late Stopping) , in children with cancer and high-risk febrile neutropenia (FN). Phase: PHASE4 Status: COMPLETED Conditions: Febrile Neutropenia Interventions: Piperacillin and Tazobactam for Injection; Cefepime Injection; Ceftazidime Injection; Vancomycin Injection; Amikacin Injection; Ciprofloxacin; Piperacillin and Tazobactam for Injection; Cefepime Injection; Ceftazidime Injection; Vancomycin Injection; Amikacin Injection; Ciprofloxacin

Haruka Yamaki, Satoshi Konishi, Koji Tamai et al.

Multiciliated cells (MCCs) are pivotal in airway defense via their motile cilia to eliminate inhaled pathogens and particles. Genetic variants in primary ciliary dyskinesia (PCD) disrupt ciliary function, resulting in chronic respiratory infections. The formation of MCCs requires centriole amplification mediated by non-membranous organelles called deuterosomes, whose regulatory mechanisms remain poorly characterized in humans. Single-cell transcriptomic analyses have identified "deuterosomal cells" (DCs), a transient cell population that emerges during multiciliogenesis. DCs are challenging to investigate owing to their scarcity. To elucidate the role of DCs, iPSC-derived airway epithelial cells were used to identify CD36 as a specific surface marker. Furthermore, iPSCs were established from a patient with PCD harboring Cyclin O (CCNO) variants, along with gene-corrected controls. Patient-derived iPSCs demonstrated defective MCC differentiation and aberrant DCs attributed to CCNO deficiency. This study provides a human iPSC-based platform for investigating the mechanisms underlying airway multiciliogenesis and PCD modeling.

Yao-Hui Sun, Daphne A Diloretto, Hillary K J Kao et al.

Cardiovascular diseases (CVDs), many of which are influenced by exposure to environmental xenobiotics, lack physiologically relevant in vitro models for cardiotoxicity assessment. Although some pollutants have established associations with CVD, the effects of a wide range of potential toxicants remains unknown. Here, we developed a three-dimensional recellularized humanized engineered heart tissue (rHHT) platform by integrating decellularized human left ventricular extracellular matrix with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), yielding spontaneously contracting tissues that recapitulate key features of native ventricular myocardium. We also generated a hiPSC line stably expressing the calcium indicator GCaMP6f, enabling real-time and longitudinal monitoring of calcium transients. Using ethanol and rotenone as examples, we demonstrate that the rHHT platform provides a sensitive system for evaluating cardiotoxicity and is more stringent than conventional monolayer approaches. This study presents a scalable platform for xenobiotic cardiotoxicity assessment, with potential applicability to high-throughput screening, mechanistic studies, and future personalized medicine applications.

Shiwei Du, Qi Long, Yanshuang Zhou et al.

Mitochondrial transplantation holds significant potential for the treatment of mitochondrial diseases. However, how to efficiently deliver exogenous mitochondria to somatic cells or tissues remains unresolved. We present a mitochondrial transplantation approach to deliver mitochondria into the cells and tissues of mice and monkeys with high efficiency, based on encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes. Treatment with encapsulated mitochondria complemented the loss, deletion, or mutation of mitochondrial DNA, thereby rescuing the associated bioenergetic and biochemical defects in patient-derived cells with mitochondrial disorders. Furthermore, mitochondrial capsules rescued the mitochondrial DNA depletion syndrome and Leigh syndrome in Dguok-/- and Ndufs4-/- mouse models, respectively. Moreover, in a mouse model of Parkinson's disease, mitochondrial capsules rescued neuron loss, improved motor skills, and restored mitochondrial function in the affected brain regions. Our study demonstrates the potential of this mitochondrial capsule as a treatment for mitochondrial disorders and proposes an "organelle therapy" strategy in regenerative medicine.

Xiaojing Chen, Zhiyuan Mao, E Motunrayo Kolawole et al.

T cells are often weakly responsive to tumor self-antigens because of central tolerance, constraining their ability to eliminate tumors. We exploited mechanical force to engineer a weakly reactive T cell receptor (TCR) specific for a nonmutated tumor-associated antigen (TAA), prostatic acid phosphatase (PAP). We identified a catch-bonding "hotspot" whose mutation enhanced T cell activity by increasing TCR-pMHC (peptide-major histocompatibility complex) bond lifetime while preserving physiological affinities and antigen fine specificities. T cells expressing these engineered TCRs showed vastly superior expansion in the tumor, effector phenotypes, and tumor elimination. Crystal structures and molecular dynamics simulations revealed a single amino acid mutation at the catch-bond hotspot primes the TCR for peptide interaction through water reorganization at the TCR-pMHC interface. Catch-bond engineering is a viable biophysically based strategy for transforming tolerized antitumor T cells into potent TCR-T cell therapy killers.

Kaiyan Zhang, Hongjun Li, Yan Zhou

Acute gastroenteritis viruses, such as rotavirus, human norovirus, human astrovirus, human adenovirus, human sapovirus, represent significant threats to global public health. Research on these pathogens has long been hampered by the limitations of conventional models. Animal and cell-based systems, widely used in virological studies, show limited efficiency in supporting rotavirus replication, while noroviruses remain largely non-cultivable in these settings. Organoids-complex, three-dimensional multicellular structures derived from stem cells-exhibit organ-specific characteristics and spatial organization, making them promising tools for viral research. Intestinal organoids, in particular, recapitulate key features of the gut epithelium and have emerged as versatile platforms for investigating viral pathogenesis and developing intervention strategies. This review systematically outlines the cultivation and functional properties of human intestinal organoids, as well as the evolution and progress of their application in studying acute gastroenteritis viruses. However, current intestinal organoid models are primarily composed of epithelial cells and lack immune and other non-epithelial components, thereby limiting their ability to fully simulate host-pathogen interactions and immune responses following infection. Future efforts should focus on incorporating emerging technologies, such as CRISPR/Cas9 gene editing, to develop more physiologically relevant intestinal models that better mimic in vivo conditions.

Na Xu, Shihao Wang, Tingting Yang et al.

Variants in OTUD5 are associated with neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain unclear. This study aimed to investigate the pathogenicity of a novel OTUD5 variant (c.697G&#x2009;>&#x2009;A, p.Val233Met) and elucidate its regulatory role in neural progenitor cell (NPC) proliferation and differentiation, thereby uncovering the function of OTUD5 in neurodevelopment.

Le Zong, Bongsoo Park, Yaqiang Cao et al.

Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we perform epigenetic profiling in male mice to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We identify a looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs which is accompanied by overexpression of a shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC and megakaryocyte progenitor (MkP) signature genes via regulating TBP binding at their promoters, which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA-mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high resolution analysis of a dysregulated HSC aging epigenome and reveal a Btaf1 variant that drives HSC aging phenotypes in mice.

Paraish S Misra, Emily C McGaugh, Haiyang Huang et al.

Knowledge of the molecular cues guiding pancreatic development is critical to developing beta cell replacement therapies for the treatment of diabetes. We compare different methods of pancreatic endocrine differentiation from human pluripotent stem cells (hPSCs) and establish sequences of patterning that can selectively increase the frequencies of islet-like or off-target enterochromaffin (EC)-like cells, thereby&#xa0;significantly&#xa0;increasing islet-like cellular yield and glucose-stimulated insulin secretion. Using a model of disrupted murine islet development that gives rise to pancreatic EC-like cells, we identify persistent Neurogenin 3 (NGN3) expression as a conserved feature associated with human and murine pancreatic EC-like cell differentiation. Finally, by comparing the phenotypes obtained through different patterning strategies, we observe that endocrine subtypes can vary significantly in their expression of canonical lineage markers. In addition to expanding our understanding of pancreatic endocrine lineage allocation and identity, these findings establish a logical differentiation framework to guide the generation of designer hPSC-islets for research and therapeutic applications.

Danny Luan, Ori Ben Valid, Ofrat Beyar-Katz et al.

Abstract Circadian rhythms orchestrate immune activation and effector function, yet whether within-day timing influences chimeric antigen receptor (CAR) T-cell therapy outcomes remains unknown. We conducted an international, multicenter retrospective study of 1052 adults with relapsed or refractory large B-cell lymphoma treated with CD19-directed CAR T-cell therapy across 7 centers (2017-2025). The median infusion time was 11:48 am (interquartile range, 11:06 am to 12:45 pm). Each hour later in infusion time was associated with an increased risk of progression, relapse, or death (hazard ratio, 1.11; 95% confidence interval, 1.03-1.20; P = .004) after adjustment for center, product, and key clinical variables. One-year progression-free survival (PFS) was 51.4% for early (before 12:00 noon) infusion vs 35.2% for late (at or after 12:00 noon) infusion, whereas overall survival was similar between groups. The PFS benefit was driven by lower relapse and higher complete response rates in the early infusion group. Although no differences were observed in immune toxicities, late infusion correlated with higher peak inflammatory markers and reduced day 7 CAR T-cell expansion. Together, these findings suggest that the timing of CAR T-cell infusion may influence therapeutic efficacy and support prospective evaluation of circadian-informed delivery strategies.

Tom van Meerten, Marie José Kersten, Gloria Iacoboni et al.

Abstract Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed/refractory (R/R) mantle cell lymphoma (MCL) based on the ZUMA-2 cohort 1 (ClinicalTrials.gov identifier: NCT02601313) study in which brexu-cel demonstrated a 93% objective response rate (ORR) and 67% complete response (CR) rate in patients with R/R MCL and previous BTKi therapy (N = 60). Here, we report the primary results of ZUMA-2 cohort 3 (brexu-cel in patients with BTKi-naive R/R MCL). Adults received brexu-cel at 2 × 106 anti-CD19 CAR T cells per kilogram. The primary end point was ORR assessed by independent radiology review committee (IRRC). As of 26 November 2023, 95 patients were enrolled, and 86 received brexu-cel; median follow-up was 15.5 months. The primary end point was met, with a 91% ORR (95% confidence interval [CI], 82.5-95.9; P< .0001; N = 86) and a CR rate of 73% (95% CI, 62.6-82.2). Estimated 12-month progression-free survival (PFS), duration of response, and overall survival (OS) rates were 75%, 80%, and 90%, respectively. Among 95 enrolled patients, the ORR was 82%, the CR rate was 66%, and the 12-month PFS and OS rates (95% CI) were 73% (62.1-80.8) and 85% (75.6-90.7), respectively. Most patients (88%) experienced treatment-related grade ≥3 adverse events, including 4 treatment-related grade 5 events. Consistent with cohort 1, brexu-cel demonstrated a high ORR and similar safety profile. These results support the continued use of brexu-cel in patients with R/R MCL, and consideration in some patients without previous BTKi therapy who have high-risk disease. This trial was registered at clinicaltrials.gov as #NCT04880434.

Gloria Iacoboni

The Methodist Hospital Research Institute

This is a phase 1/2 single center, pilot study to assess safety and efficacy of allogeneic adipose-derived mesenchymal stem cells (HB-adMSCs) and to evaluate the timing and combination effects of active treatment versus placebo in promoting the recovery of erectile function in patients undergoing radical retropubic prostatectomy (RALP) of localized prostate cancer. Phase: PHASE1, PHASE2 Status: NOT_YET_RECRUITING Conditions: Erectile Dysfunction; Prostate Cancer Interventions: Allogeneic adipose-derived mesenchymal stem cells (HB-adMSCs) at the doctor's office; Allogeneic adipose-derived mesenchymal stem cells (HB-adMSCs) in the OR; Placebo in the OR; Placebo in clinic

Shanghai Zhongshan Hospital

Graves' disease is an autoimmune thyroid disorder characterized by the production of autoantibodies against the thyroid-stimulating hormone receptor (TRAb), leading to excessive thyroid hormone secretion and systemic manifestations. A subset of patients develop refractory disease, failing to achieve durable remission despite prolonged antithyroid therapy. This study aims to evaluate the safety and efficacy of HN2301, an in vivo CAR-T therapy in which host T lymphocytes are engineered and transformed to functional CAR-T cells via CD8 antibody-coated LNP delivery of CD19 CAR-mRNA. Participants with refractory Graves' disease will receive three to five administrations of HN2301 and will be regularly monitored for changes in thyroid function, TRAb levels, clinical response, and treatment-related adverse events. The study will provide preliminary evidence on whether HN2301 can induce sustained remission of refractory Graves' disease. Phase: EARLY_PHASE1 Status: RECRUITING Conditions: Graves' Disease Interventions: In Vivo CAR-T Therapy

jCyte, Inc

This study evaluates the safety of a single injection of jCell (famzeretcel) comprising 6.0 million (6.0M) retinal progenitor cells over a six-month study period in a cohort of adult subjects with RP. Additionally, changes in visual function will be evaluated at six months between the active treatment group (6.0M jCell) compared to sham-treated controls. Phase: PHASE2 Status: RECRUITING Conditions: Retinitis Pigmentosa Interventions: human retinal progenitor cells; Mock injection

Second Affiliated Hospital, School of Medicine, Zhejiang University

In the era of novel therapeutic agents, high-dose conditioning chemotherapy combined with autologous hematopoietic stem cell transplantation (auto-HSCT) remains an important and feasible consolidation strategy for non-Hodgkin lymphoma, especially for high-risk and relapsed/refractory patients. It can effectively prolong progression-free survival and even overall survival in chemotherapy-sensitive lymphoma patients, and its application in domestic clinical practice has become increasingly widespread. With long-term and extensive use of carmustine-based conditioning regimens, their limitations have become increasingly apparent: the drug is expensive and has limited accessibility. Early treatment-related toxicities include mucositis, nausea, vomiting, diarrhea, and hepatotoxicity. Late toxicities include reduced pulmonary diffusion capacity, chronic interstitial pulmonary fibrosis, metabolic syndrome, and cardiovascular complications, all of which have attracted increasing attention. Thiotepa, a cell-cycle-nonspecific alkylating agent, not only inhibits DNA synthesis and kills tumor cells but also readily crosses the blood-brain barrier, has a short half-life and rapid metabolism, and its safety has been widely confirmed in clinical practice. It is an ideal agent for transplant conditioning. In recent years, various thiotepa-based conditioning regimens have been used in auto-HSCT for different types of non-Hodgkin lymphoma, achieving favorable efficacy and safety profiles, and can partially replace the classic BEAM regimen. Investigators at our center observed that among non-Hodgkin lymphoma patients eligible for auto-HSCT, some have involvement at special sites, such as the central nervous system, nerve roots inside or outside the spinal canal, reproductive organs (uterus, ovary, breast, testis), kidney/adrenal gland, and multiple extranodal sites (bone, colorectum), all of which confer a high risk of central nervous system recurrence. Meanwhile, the high cost of thiotepa limits its clinical use. To benefit more patients with CNS-high-risk lymphoma, our center has adjusted the dosage of the existing TEAM regimen. In a 4-year retrospective study, 29 lymphoma patients with involvement at the above sites received modified TEAM conditioning chemotherapy followed by auto-HSCT. With a maximum follow-up of 3 years, 2 patients died of disease progression, 1 patient remained in stable condition after radiotherapy for relapse, and all other patients achieved long-term survival with stable disease. Therefore, our center is applying to conduct a prospective study of this conditioning regimen to obtain more convincing clinical evidence, provide a stronger theoretical basis for auto-HSCT conditioning for more CNS-high-risk lymphoma patients, and explore a more effective, less toxic, and cost reasonable therapeutic strategy. Phase: PHASE2 Status: RECRUITING Conditions: Lymphoma Patients With High-risk of Central Nervous System Relapse Interventions: TEAM regimen (thiotepa, etoposide, cytarabine and melphalan)

UTC Therapeutics Inc.

This is a single-arm, open-label, exploratory clinical study to evaluate the safety and preliminary efficacy of Anti-HER2 CAR-T cell injection in patients with HER2-positive advanced malignant solid tumors. Phase: NA Status: RECRUITING Conditions: HER2-positive Advanced Malignant Solid Tumors Interventions: Anti-HER2 CAR-T cells

DiscGenics, Inc.

This is a Phase III, randomized, double-blinded, Sham-controlled, multi-center study in subjects with single-level, symptomatic lumbar (L3- S1) intervertebral disc degeneration. The study will have a 52-week primary period followed by 52 week Follow-up Period (total of 104 weeks). The study protocol will be approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), and the study will be conducted in accordance with Good Clinical Practice (GCP). All subjects will provide written informed consent prior to Screening. Approximately 162 subjects will be enrolled in the study. Up to 45 days prior to treatment, subjects will be screened for study inclusion, which includes obtaining baseline MRI and X-ray imaging. Imaging results for subjects initially eligible for study participation will be sent to a central imaging vendor for review and confirmation of eligibility, including the number of levels with degeneration. Subjects meeting all inclusion/exclusion criteria will be assigned to the corresponding treatment arm group and subsequently randomized to IDCT or Sham. Randomization will occur approximately 7 to 14 days prior to the scheduled treatment administration date. Overall, 162 subjects will be enrolled and randomized to IDCT or Sham in a 2:1 ratio. * IDCT (n=108) * Sham (n=54) Phase: PHASE3 Status: RECRUITING Conditions: Degenerative Disc Disease Interventions: IDCT (rebonuputemcel); Sham (No Treatment)

Jingjing Wu, Ying Ge, Li Zhang et al.

Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer's disease mouse model (3&#xd7;Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3&#xd7;Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.

Andrew M Fleming, Carolyn M Jablonowski, Hongjian Jin et al.

Children with favorable-histology Wilms tumor (FHWT) who relapse or whose tumors show blastemal predominance post-chemotherapy often face poor outcomes. The purpose of this study is to identify mechanisms of chemotherapy resistance in FHWT. We induce a patient-derived xenograft model (KT-47) to develop blastemal predominance after chemotherapy and to become resistant to vincristine, actinomycin-D, and doxorubicin (VAD). Multi-omics analyses reveal chromatin and transcriptional changes, including increased H3K4me3 and decreased H3K27me3 at stem cell and nephrogenesis gene loci. LIN28B is the most upregulated resistance-associated gene, linked to MYCN copy gain/upregulation and chromatin remodeling. ABCB1 expression correlates with interchromosomal enhancer interactions and functions as the mediator of chemotherapy resistance in vitro. These findings are validated in additional Wilms tumor models. Overall, resistance is associated with de-differentiation to a stem-like state and is driven by ABCB1 upregulation, suggesting that therapeutic strategies targeting chromatin regulation and drug efflux may be relevant in therapy-resistant Wilms tumor.

Qi Shao, Zhenghao Li, Weixing Tan et al.

Insufficient maturation of oligodendrocyte progenitor cells (OPCs) contributes to the failure of endogenous remyelination in multiple sclerosis (MS). It remains unclear whether dysregulated oligodendroglial microRNAs (miRNAs) impede remyelination in chronic MS lesions. In this study, we demonstrated that miR-126a-3p was enriched in oligodendroglia from chronic inactive MS plaques and chronic lesions in mice with experimental autoimmune encephalomyelitis (EAE). Functional analyses revealed that miR-126a-3p inhibited OPC differentiation in vitro and that the specific deletion of miR-126a-3p in oligodendroglia accelerated the remyelination process in the EAE and lysolecithin-induced demyelination models. Mechanistically, miR-126a-3p exerted an inhibitory effect on OPC differentiation and remyelination by directly targeting peroxin-5 ( Pex5 ) transcripts. A screening of a US Food and Drug Administration–approved drug library based on Pex5 levels led to the identification of ganciclovir, an antiviral agent, as a potent proremyelinating agent after in vivo demyelinating events. These results identify the aberrant miR-126a-3p– Pex5 axis in oligodendroglia as a potential therapeutic target to facilitate remyelination in chronic MS lesions.

Alexandros Sountoulidis, Jonas Theelke, Andreas Liontos et al.

Abstract Secretory cells are major structural and functional constituents of the lung airways. Their heterogeneity, spatial organization and specification mechanisms are partially understood. Here, we analyze secretory lung cell-types at single-cell resolution. In the airway epithelium, we find opposing, partially overlapping gene-expression gradients along the proximal-distal airway axis superimposed on a general gene program encoding detoxification. One graded program is elevated proximally and relates to innate immunity, whereas the other is enriched distally, encoding lipid metabolism and antigen presentation. Intermediately positioned cells express moderate levels of both graded programs creating a differentiation continuum towards each end. Lineage tracing analysis during development reveals the sequential establishment of the gradients in common epithelial progenitors postnatally. We show that Fgfr2b regulates the airway patterning by inducing and maintaining high levels of lipid biosynthesis and vesicle trafficking in distal airways and down-regulating innate-immunity genes in vivo and in airway organoids. Our analysis offers a framework for studying epithelial and lung tissue organization to better understand cellular roles in tissue-level pathology.

Stefan J. Hutten, Xue Chao, Madelon Badoux et al.

Targeted therapies are important for invasive breast cancer (IBC) treatment but are generally not standard of care in the neoadjuvant setting. To identify therapies with the potential to improve neoadjuvant treatment response, it is essential to develop patient-derived preclinical models that faithfully reflect the diversity of primary IBC subtypes in patients. Here, we generated and characterized a large-scale cohort of 60 mouse-intraductal patient-derived xenograft (MIND-PDX) models representing all subtypes of primary IBC, as well as seven matched PDX-derived organoids. We showed that our IBC-MIND cohort can serve as a platform for preclinical evaluation of experimental neoadjuvant treatments. For triple-negative IBC, we demonstrated that neoadjuvant treatment does not benefit from addition of a PARP inhibitor, whereas for estrogen receptor–positive IBC, the combination of a CDK4/6 inhibitor and fulvestrant improved neoadjuvant treatment response. Our work provides a valuable resource of primary IBC models to study breast cancer biology and develop neoadjuvant treatments.

Abramson Cancer Center at Penn Medicine

The research study is being conducted to test the safety and effectiveness of the experimental drug mosunetuzumab (Cohort 1) or obinutuzumab and glofitamab (Cohort 2) when given after CAR (genetically modified) T cells. The study is for patients who have already received a CAR T-cell infusion. Some patients who join the study will receive mosunetuzumab, other patients later in the study may receive a different experimental drug (glofitamab, in combination with obinutuzumab). Phase: PHASE2 Status: RECRUITING Conditions: Large B-cell Lymphoma; DLBCL - Diffuse Large B Cell Lymphoma Interventions: mosunetuzumab; glofitamab; obinutuzumab

Ospedale San Raffaele

The goal of this interventional study is to generate induced pluripotent stem cells (iPSCs) from somatic cells and differentiate them into insulin-producing β cells in patients with metabolic and genetic pancreatic diseases and in healthy controls. The main questions it aims to answer are: Can somatic cells from healthy individuals and patients with diabetes be successfully reprogrammed into iPSCs? Can these iPSCs be differentiated into functional insulin-producing β cells suitable for studying disease mechanisms and developing cell-based therapies? Participants will provide a single biological sample (either a 3 mm skin punch biopsy, a blood sample, or a urine sample) collected under sterile conditions. The samples will be used to derive somatic cells, which will then be reprogrammed into iPSCs and differentiated into β cells for laboratory analyses. Participants will: Undergo a one-time sample collection (skin biopsy, blood draw, or urine collection) at Ospedale San Raffaele Receive standard post-procedure care (if applicable) This research aims to improve understanding of β cell function and dysfunction in diabetes and to advance personalized regenerative therapies for β cell replacement. Phase: NA Status: RECRUITING Conditions: Diabetes Interventions: Biological - skin biopsy, blood draw, or urine collection for iPSC generation

BioCytics, Inc.

Primary Objective: This is a study to investigate the feasibility of harvesting, expanding, and selecting T lymphocytes from cancer patients and healthy volunteers. The preliminary objective of this study is aimed at selecting PD-1+ and CTLA4+ T cells and other cellular fractions from peripheral blood of cancer patients and healthy volunteers by using specific conjugated antibodies, evaluating their functional ex vivo anti-tumor cytotoxicity against targeted autologous tumor cells. Status: RECRUITING Conditions: Solid Tumor, Adult; Healthy Donors; COVID-19 Donors

Centre Oscar Lambret

From a cellular perspective, breast cancers appear to develop hierarchically from a small contingent of cancer stem cells (CSCs). The presence of CSCs in tumor tissue is associated with an increased risk of recurrence and metastasis, as well as a worse prognosis. Thus, these CSCs exhibit resistance to conventional anti-tumor treatments such as radiotherapy and chemotherapy. Moreover, these treatments would favor the emergence of these CSCs and the reprogramming of non-CSCs in CSCs. It has been demonstrated in neoadjuvant that the proportion of CSCs before any treatment is correlated with chemoresistance and that a resurgence of CSCs after chemotherapy is correlated with a poor prognosis. However, the mechanisms involved in the emergence of CSCs by reprogramming of non-CSCs are not yet known. The Oscar Lambret Center proposes a monocentric prospective interventional study based on the cellular and molecular analysis of the tumor, serum and circulating cells, before, during and at the end of the treatment for each patient receiving a neoadjuvant chemotherapy for breast cancer. The identification of the mechanisms contributing to the enrichment of CSCs resistant to chemotherapy could lead to therapeutic solutions. Phase: NA Status: TERMINATED Conditions: Breast Cancer Interventions: Biological collection

The Methodist Hospital Research Institute

This study is designed as a prospective, open label, single arm pilot clinical study that will establish the safety and efficacy of a single injection of mesenchymal stromal cells in patients. Each subject will receive one intra-articular injection of autologous mesenchymal stromal cells derived from infrapatellar fat pad (FP-MSC) tissue samples collected from the subject during anterior cruciate ligament (ACL) reconstruction surgery. Phase: PHASE1 Status: RECRUITING Conditions: Anterior Cruciate Ligament Reconstruction Interventions: Autologous Mesenchymal Stromal Cells

Hospital Universitario La Paz

This randomized controlled clinical trial evaluates neurocognitive, biopsychological, and brain connectome outcomes in children and adolescents with acute lymphoblastic leukemia who have previously received Chimeric Antigen Receptor T-cell therapy (CAR T-cell therapy), chemotherapy, and/or hematopoietic stem cell transplantation (HSCT). Participants will receive a multimodal, telematic psychological intervention combining digital cognitive training and an adapted mindfulness-based emotional regulation program. Outcomes will be compared with a waitlist control group and intervention sequences will be counterbalanced: (1) cognitive training followed by mindfulness; and (2) mindfulness followed by cognitive training. Neurocognitive performance, emotional-behavioral functioning, executive functioning and EEG-based functional connectivity will be assessed at baseline, post-intervention and at 6 months follow-up. Phase: NA Status: RECRUITING Conditions: Acute Lymphoblastic Leukemia Interventions: Digital cognitive training; Online Mindfulness-Based Intervention

Boston Children's Hospital

The goal of the Precision Diagnosis in Inflammatory Bowel Disease, Cellular Therapies, and Transplantation (PREDICT) trial is to apply a systems-biology approach to enable precision diagnostics for the key immunologic outcomes for patients with Inflammatory Bowel Disease, Cellular Therapeutics and Transplantation. This approach will deepen the understanding of the molecular mechanisms driving auto- and allo-immune diseases and serve as a critical platform upon which to design evidence-based treatment paradigms for these patients. This research study will examine the immunology of auto- and allo-immune gastrointestinal disturbances such as Inflammatory Bowel Disease (IBD), Graft-versus-Host Disease (GVHD), and Functional Gastrointestinal Disorder (FGID), as well as the immune manifestations after CAR-T and other cellular therapeutics. The Investigators seek to use blood and tissue samples in order to better understand the mechanisms driving these diseases and their therapies. The Investigators further hypothesize that longitudinal systems-based immunologic analysis will enable the patient-specific determination of the molecular evolution of IBD, GVHD and the response to cellular therapeutics, as well post-transplant defects in protective immunity, and determine which pathways, when perturbed, can cause clinical disease. The discovery of these pathways will lead to improved diagnostic, prognostic and treatment approaches, and to personalized therapeutic decision-making for these patients. Status: ENROLLING_BY_INVITATION Conditions: Graft Vs Host Disease; Inflammatory Bowel Diseases; Functional Gastrointestinal Disorders

Ankara City Hospital Bilkent

The goal of this prospective randomized controlled clinical study is to evaluate the effectiveness and safety of intracavernosal injections of umbilical cord-derived mesenchymal stem cells (MSCs) and umbilical cord-derived MSC-derived exosomes in men aged 25 to 75 years with diabetic erectile dysfunction (ED) who have not responded adequately to conventional medical treatments such as phosphodiesterase type-5 (PDE-5) inhibitors. Diabetes mellitus is a major risk factor for erectile dysfunction and is associated with endothelial dysfunction, impaired smooth muscle relaxation, neuropathy, and increased fibrosis within penile tissue. Although many patients respond to standard pharmacological treatments, diabetic patients often demonstrate reduced responsiveness to these therapies. Regenerative medicine approaches, including stem cell therapy and stem cell-derived exosomes, have emerged as potential therapeutic strategies due to their regenerative, angiogenic, neuroprotective, and anti-fibrotic effects. The main questions this study aims to answer are: * Whether intracavernosal administration of mesenchymal stem cells or MSC-derived exosomes improves erectile function, as measured by changes in the International Index of Erectile Function-5 (IIEF-5) and Erectile Hardness Score (EHS). * Whether penile hemodynamics improve following treatment, as assessed by penile Doppler ultrasonography parameters including peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI). Participants will be randomly assigned to one of three groups: * Intracavernosal placebo injection * Intracavernosal injection of umbilical cord-derived mesenchymal stem cells (5×10⁶ cells) * Intracavernosal injection of umbilical cord-derived mesenchymal stem cell-derived exosomes (75 μg) All interventions will be administered as a single intracavernosal injection under controlled clinical conditions. Participants will undergo baseline evaluation including medical history, physical examination, erectile function assessment using the IIEF-5 questionnaire, and penile Doppler ultrasonography. Follow-up evaluations will be conducted at 1, 3, 6, and 12 months after treatment to assess changes in erectile function, penile vascular parameters, and treatment-related adverse events. The study will also monitor potential side effects such as pain, bruising, hematoma, edema, or other complications related to the intracavernosal injection procedure. Participants will be recruited from patients presenting to the urology outpatient clinic with diabetic erectile dysfunction. Eligible participants must have a diagnosis of erectile dysfunction for at least six months, a history of diabetes mellitus for at least five years, and insufficient response to standard medical therapy. Patients with penile anatomical deformities, active infections, malignancy, unstable cardiovascular disease, autoimmune disease, or other contraindications to intracavernosal treatment will be excluded. Phase: PHASE2, PHASE3 Status: RECRUITING Conditions: Erectile Dysfunction With Diabetes Mellitus Interventions: Umbilical Cord-Derived Mesenchymal Stem Cells; Umblical Cord-Derived Mesenchymal Stem Cell-Derived Exosomes; Placebo Intracavernosal Injection

Yahui Ding, Wanqi Fang, Ruiqing Xiang et al.

Although cancer immunotherapy has recently revolutionized treatment, the low response rate to existing immune checkpoint blockade (ICB) underscores the need for new druggable targets. Here, we find that SOAT1 is selectively expressed in cancer stem cell (CSC) and pharmacological inhibition with STK results in robust anti-tumor effects across various preclinical mouse models, including colon, liver, lung, breast, and melanoma cancer, with low toxicity. Mechanistically, treatment with STK (or gene knockdown of Soat1) induces the release of 20(S)-Hydroxycholesterol (20SOHC) from the tumor cells, and downstream activation of the trans-cellular 20SOHC (tumor)- GPR132 pathway in regulatory T cell (Treg), ultimately resulting in the suppression of Treg functions and enhanced dendritic cells and cytotoxic CD8+ T cell responses. Importantly, STK treatment synergizes with anti-PD-1 or anti-CTLA-4 ICB therapy. Thus, our findings identify SOAT1 as a CSC metabolism checkpoint that facilitates immune evasion and SOAT1 inhibition as a promising strategy for advanced cancer immunotherapy.

Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

The purpose of this study is to evaluate the efficacy, safety and drug levels of CC-97540 in participants with active systemic lupus erythematosus (SLE) including lupus nephritis with inadequate response to glucocorticoids and at least 2 immunosuppressants. Phase: PHASE2 Status: RECRUITING Conditions: Lupus Erythematosus, Systemic; Lupus Nephritis Interventions: CC-97540; Fludarabine; Cyclophosphamide

Lisa Zipper, Pol Ramon-Ca&#xf1;ellas, Filiz Akkas-Gazzoni et al.

Adult epithelial organs undergo continual steady-state turnover that is achieved by tight coupling of stem cell production with replacement of worn-out epithelial cells by local intercellular signalling1,2. Like many eukaryotic epithelia, absorptive enterocytes (EC) of the adult Drosophila midgut are arranged in a hexagonal, honeycomb-like pattern. On tricellular nexuses of EC, intestinal stem cells (ISC) are scattered in a way so that around two thirds of EC can be renewed directly by adjacent ISC. However, the mechanism for replacement of the remaining third of remotely located EC is unknown.Here, we show that a conserved axonal guidance cue directs enteroblasts (EB), the immediate ISC daughters, to selectively replace worn-out adjacent and remote EC with identical frequency. Worn-out EC express Netrin-B ligands that attract Frazzled/DCC-receptor dependent EB protrusions and subsequent EB migration towards the Netrin-B expressing EC. Our newly developed 'Hamelin' assay confirms Frazzled-dependent EB migration towards Netrin-B sources and hints to invasive progenitor behaviour as midgut progenitors cross the organ boundary into the hindgut. Together, we establish spatially directed EB migration and integration as essential for intestinal homeostasis and provide first mechanistic support for recent findings resuscitating conserved Netrins and Frazzled/DCC-signalling as therapeutic target in metastasis.

Astellas Institute for Regenerative Medicine

The purpose of this study is to is to evaluate the occurrence of late onset (i.e., greater than 5 years after treatment) adverse events of special interest (AESI) in participants who have received sub-retinal transplant of human embryonic stem cell derived - retinal pigment epithelial (hESC-RPE) cells in an AIRM-sponsored clinical trial. The events of special interest are adverse events (AEs) that are presumed to have a potential causal relationship to the hESC-RPE cells. Phase: PHASE1, PHASE2 Status: ENROLLING_BY_INVITATION Conditions: Macular Degenerative Disease Interventions: Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells

Janssen Research & Development, LLC

The purpose of this study is to evaluate the overall minimal residual disease (MRD) negative rate of participants who receive JNJ-68284528. Phase: PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple Myeloma Interventions: JNJ-68284528; Lenalidomide; Daratumumab; Bortezomib; Dexamethasone

Zecheng Zhong, Weida Huang, Jinhua Ren et al.

MicroRNAs are promising liquid biopsy biomarkers, but their clinical translation is hindered by detection challenges, including low abundance, high sequence similarity, and background interference. Here we present SE-SPTM-PCR, a detection platform integrating selective miRNA enrichment using locked nucleic acid probes with specific probe terminal mediated RT-qPCR. We show that SE-SPTM-PCR eliminates nonspecific amplification and achieves 100-fold higher sensitivity than conventional stem-loop RT-qPCR. In clinical studies, SE-SPTM-PCR significantly improves hsa-miR-92a-3p performance for colorectal cancer detection, increasing its AUC from 0.72 to 0.85 in 48 patients versus 48 controls. Additionally, SE-SPTM-PCR also restores utility to two abandoned biomarkers: For HCMV reactivation monitoring in 32 DNA positive and 32 DNA negative hematopoietic stem cell transplant recipients, hcmv-miR-UL22A-5p achieves an AUC of 0.95. For nasopharyngeal carcinoma, ebv-miR-BART3-3p reaches a perfect AUC of 1.0 in 40 patients and 40 controls. This platform provides a robust tool for miRNA-based liquid biopsy, offering enhanced diagnostic accuracy to support early disease detection and personalized treatment strategies.

Apriligen, Inc.

Brief summary The goal of this clinical trial is to learn if APR-2020 is safe and can help treat Diamond-Blackfan Anemia (DBA) in adolescents and children. The main questions it aims to answer are: * Is APR-2020 safe and well tolerated? * Does APR-2020 modify or correct an underlying genetic condition which causes DBA? * Does APR-2020 reduce or eliminate the need for blood transfusions and/or restore certain blood counts affected by DBA? Participants will: * Take the drug one time as an infusion. * Undergo two rounds of a cellular harvest procedure in which their own cells will be used in the manufacturing of their own participant-specific product. * Initially return to the clinic for two years of follow up at increasingly sparse intervals. Phase: PHASE1 Status: RECRUITING Conditions: RPS19 Deficient Diamond-Blackfan Anemia Interventions: APR-2020

Washington University School of Medicine

This single arm pilot phase I study with safety run-in is designed to estimate the safety and efficacy of a familial mismatched or haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using a novel graft modification technique (selective αβ-TCR and CD19 depletion). Phase: PHASE1 Status: RECRUITING Conditions: Pediatric Hematologic Malignancies Interventions: Ex Vivo T-cell receptor alpha-beta and CD19+ Depletion using CliniMACs Plus

Pulin Yan, Jian He, Yongwei Huang et al.

Intervertebral disc (IVD) degenerative disease is a prevalent and debilitating spinal disease. Current treatments only focus on symptomatic relief but fail to halt disease progression or restore the native biomechanical function of the spine. Regenerative medicine strategies, particularly those harnessing endogenous progenitor cells, offer a promising avenue for achieving biological repair and functional homeostasis. The identification of intervertebral disc progenitor cells (IVD-PCs) has unveiled a potential cellular reservoir for self-repair, given their demonstrated stemness attributes, including clonogenicity and multipotent differentiation. However, the clinical translation of IVD-PCs is significantly hampered by an incomplete understanding of their inherent heterogeneity, hierarchical organization, and, most critically, the dynamic interplay with their unique microenvironment, which dictates their fate decisions. This review synthesizes recent advances in deciphering the molecular signatures and functional plasticity of IVD-PCs. We place a particular emphasis on how key physicochemical, mechanical, and cellular cues within the IVD niche orchestrate progenitor cell behavior-ranging from maintenance and activation to aberrant differentiation-during both homeostasis and degeneration. Furthermore, we propose forward-looking insights to bridge critical knowledge gaps, aiming to propel the development of novel progenitor cell-based therapeutics for IVD degeneration.

Janssen Research & Development, LLC

The purpose of this study is to compare the efficacy of ciltacabtagene autoleucel (cilta-cel) with standard therapy, either Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd). Phase: PHASE3 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple Myeloma Interventions: Cilta-cel; Pomalidomide; Bortezomib; Dexamethasone; Daratumumab

Ensoma

The goal of this clinical trial is to evaluate the safety and potential efficacy of the EN-374 treatment regimen and identify a dose level for further evaluation in participants with x-linked chronic granulomatous disease. The main questions it aims to answer are: * safety of the EN-374 treatment regimen * effect of the EN-374 treatment regimen on the production of functional neutrophils with NADPH oxidase activity Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: X-Linked Chronic Granulomatous Disease Interventions: EN-374

AvenCell Therapeutics, Inc.

The goal of this clinical study is to learn more about the long-term safety, effectiveness and prolonged action of patients who participated in an AvenCell-sponsored clinical trial and received treatment with AvenCell's UniCAR or RevCAR platforms. Status: ENROLLING_BY_INVITATION Conditions: B-cell Lymphoma; Chronic Lymphocytic Leukemia; Hematologic Malignancy; AML (Acute Myelogenous Leukemia); Prostate Cancer Interventions: UniCAR02-T (IMP) With Targeting Module TM123; UniCAR02-T-pPSMA; Allo-RevCAR01- T with Targeting Module R-TM123; Allo-QuadCAR01-T

Zhejiang University

An open label, dose-escalation clinical study to evaluate the safety, anti-tumor activity and pharmacokinetics/pharmacodynamic (PK/PD) of NW-301VT in subjects with advanced solid tumor. Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Tumor Interventions: NW-301VT

CellinCells

The purpose of this clinical trial was to evaluate the safety and efficacy of a single administration of TRTP-101 in adults with atrophic scars. Phase: PHASE1, PHASE2 Status: NOT_YET_RECRUITING Conditions: Atrophic Scar Interventions: TRTP-101; Placebo

Marcela V. Maus, M.D.,Ph.D.

This is a single site, non-randomized, open-label, long-term safety and efficacy follow-up study for Phase 1 studies that evaluate the safety and efficacy of CAR T cells: NCT05660369 (DF/HCC# 22-175) and NCT06026319 (DF/HCC# 23-474). Status: RECRUITING Conditions: Long Term Adverse Effects; CAR-T; Duty to Follow Up; Adult; Progression-Free Survival; Disease-Free Survival; Overall Survival Interventions: Disease assessments; Tumor Biopsy; Blood test

Huiying Shi, Hailing Yao, Yilin Liu et al.

Lucy J Cornell, Caroline L Harrold, Susannah Holliman et al.

Abstract The mammalian genome is organised into large topologically associating domains (TADs) and smaller sub-TADs or enhancer-promoter loops, which may contribute to the regulation of gene expression. These dynamic structures arise, at least partly, via cohesin-mediated loop extrusion delimited by insulator elements. By studying the structure and function of the alpha-globin locus during erythroid differentiation, we have previously shown that the juxtaposition of the enhancers and promoters during this process partly depends on cohesin-mediated loop extrusion, which appears to be delimited by 12 largely convergently orientated CTCF boundary elements. To define the downstream boundary of the sub-TAD, we removed four CTCF sites in informative combinations. This showed that rather than CTCF insulators, it is the transcriptionally active alpha-globin gene that defines the downstream boundary of the sub-TAD. Further, insertion of actively transcribed fragments of the α-globin gene between the enhancers and native genes leads to a reduction in native α-globin expression and accumulation of cohesin at the insertion site. This highlights an overlap in the functional role of the fundamental elements of the genome.

The Lymphoma Academic Research Organisation

This study is a multicenter phase II trial including 2 cohorts of patients in Refractory/Relapse disease at least 1 month after CAR T-cells therapy: * cohort 1: DLBCL patients * cohort 2: PMBL, mantle cell lymphoma, transformed indolent NHL (t-iNHL) or iNHL CAR T-cells Refractory/Relapse status will be determined by PET-CT central review allowing inclusion in this trial. Patients enrolled will then receive a pre-phase of obinutuzumab followed by experimental treatment:11 cycle of glofitamab. The primary objective of the study is to assess the anti-lymphoma activity of glofitamab, a bispecific CD3xCD20 monoclonal antibody in patients with relapse/refractory DLBCL (cohort 1) disease after anti-CD19 CAR T-cells therapy Phase: PHASE2 Status: COMPLETED Conditions: Diffuse Large B-Cell Lymphoma Refractory; Refractory Indolent Adult Non-Hodgkin Lymphoma; Refractory Transformed B-cell Non-Hodgkin Lymphoma; Refractory Primary Mediastinal Large B-Cell Cell Lymphoma; Refractory Mantle Cell Lymphoma Interventions: Obinutuzumab; RO7082859

Sara Ortica, Miguel Martinez Herrera, Louis Degroux et al.

In the adult brain, Notch3 signaling promotes neural stem cell (NSC) quiescence and stemness. It remains unknown how Notch3 signaling levels are controlled and relate to these NSC decisions. Here we directly measure the nuclear translocation of the Notch3 intracellular fragment (N3ICD) and quantify Notch3 signaling in NSCs of the zebrafish adult telencephalon in situ. We report that Notch3 signaling levels match NSC quiescence and stemness levels. In physical space, Notch3 signaling is patterned and high signaling levels surround N3ICDlow cells, which also express the deltaA (dla) ligand. Another ligand, jagged1b (jag1b), expressed in all NSCs, activates Notch3 signaling and sustains expression of the stemness factor Sox2. Finally, lowering jag1b preserves the structured distribution of Notch3 signaling levels in space but attenuates their variance. We propose that Notch3 signaling integrates Dla-mediated lateral inhibition and Jag1b-mediated lateral induction to control quiescence and stemness and their spatiotemporal dynamics in adult NSCs.

Laura E K&#xf6;nig, Steve Rodriguez, Clemens Hug et al.

Neuroinflammation is a pathological feature of neurodegenerative diseases like Alzheimer's disease and ALS. Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to their death, and is found in neurons of C9ORF72-ALS patients. Here, we report the spatial coincidence of cdsRNA and pTDP-43 inclusions in human postmortem tissue with Alzheimer's disease pathology, and upregulated interferon response genes in affected regions. CdsRNA also accumulates in a human TDP-43 G298S iPSC cortical neuronal model. We use cryptic exon detection as a proxy for TDP-43 mislocalization and demonstrate that FDA-approved JAK inhibitors baricitinib and ruxolitinib, which block interferon signaling, show protective effects only in brains with elevated cryptic exon expression. A CRISPR screen reveals TYK2 as a top hit, and TYK2 knockdown and the selective TYK2 inhibitor deucravacitinib rescue cdsRNA-induced toxicity. We find parallel neuroinflammatory mechanisms, dependent on TYK2 - a potential disease-modifying target - for TDP-43-associated Alzheimer's disease and C9ORF72-ALS.

Tao Xu, Soumya Sethi, Christoph Drees et al.

Abstract Cells interpret mechanical cues from their microenvironment with spatiotemporal precision to guide adaptive behaviors. However, engineering synthetic mechanosensing systems with both cell-specificity and programmability remains challenging, especially when targeting ubiquitous classical mechanoreceptors. Here, we introduce an all-DNA mechanosensing platform based on aptamers that transmit force through noncanonical surface receptors. Aptamer–receptor recognition acts as a molecular gate for force transduction, enabling the design of mechanoprobes with cell-type selectivity. These probes interpret diverse mechanical inputs via distinct mechanisms, including actomyosin-driven contractility and membrane ruffling during macropinocytosis. By integrating aptamer mechanoprobes with upstream DNA reaction networks, we achieve reversible and temporally programmable mechanoresponses. This modular, all-nucleic-acid system offers a general framework for constructing tunable mechanotransduction circuits. It expands the design space for synthetic mechanobiology and provides opportunities for autonomous, multi-layered mechanical–biochemical regulation in tissue engineering, morphogenesis, and dynamic cell programming.

Mark A Aminzadeh, Russell G Rogers, Mario Fournier et al.

City of Hope Medical Center

This trial studies the impact of a 12-month invention focused on early detection of skin cancer and timely follow up in patients who underwent stem cell transplant and their primary care providers. Some stem cell transplant survivors may develop complications related to the treatment they received. Many of these complications may not be known for years after the treatment and preventive measures can be taken to reduce the chances that a complication will occur and encourage early detection. This study focuses on one complication that stem cell transplant survivors are at high risk of developing - skin cancer. An early diagnosis of skin cancer is important since the cancer is usually smaller, requires less extensive treatments, and has better outcomes. Teaching skin self-examination and encouraging patients to alert doctors to skin changes may provide an important opportunity for early detection of skin cancer. Phase: NA Status: ACTIVE_NOT_RECRUITING Conditions: Skin Carcinoma Interventions: Computer-Assisted Intervention; Dermatoscope; Educational Intervention; Educational Intervention (Physician); Questionnaire Administration; Text Message

Poseida Therapeutics, Inc.

Phase 1 study comprised of open-label, dose escalation, multiple cohorts of P-BCMA-ALLO1 allogeneic T stem cell memory (Tscm) CAR-T cells in subjects with relapsed / refractory Multiple Myeloma (RRMM). Phase: PHASE1 Status: RECRUITING Conditions: Multiple Myeloma Interventions: P-BCMA-ALLO1 CAR-T cells; Rimiducid; Methotrexate

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Background: Hematopoietic stem cell transplant (HSCT) is a common treatment for many cancers and other illnesses. But many people who have HSCT go on to develop liver dysfunction. Researchers want to know more about how and why this happens. In this natural history study, they will try to learn what factors lead to liver dysfunction; how underlying liver disease may affect the results of HSCT; and how HSCT may contribute to liver dysfunction. Objective: To understand the links between HSCT and liver dysfunction. Eligibility: Adults aged 18 years or older and children 3 to 17 years who are being evaluated for HSCT. Design: This study involves 11 visits in 4 years. Most visits will be in the first year. Before and after their HSCT, participants will undergo these tests: Physical exam, including blood tests and a test of heart function. Participants will provide stool samples. Liver biopsies. Samples of liver tissue will be removed. This may be done either by inserting a needle through the right side of the chest, or with a thin tube threaded to the liver from a vein in the neck. Adult participants will undergo this procedure 2 times: once before the HSCT and once about a year later. Imaging scans. Participants will lie on a bed that moves into either a cylinder or a donut-shaped machine. Ultrasound. Participants will lie still. A probe that uses sound waves will be slid over their skin to get pictures of the liver. Fibroscan exam. This is like an ultrasound that uses a special probe to measure the toughness of the liver. ... Status: NOT_YET_RECRUITING Conditions: Hematopoietic Stem Cell Transplant

Jinah Yoon, Sukhyang Lee, Jung-Hyun Kim

South Korea's Act on the Safety of and Support for Advanced Regenerative Medicine and Advanced Biological Products, enacted in 2019, was recently amended. This article examines the new advanced regenerative medicine treatment (ARMT) category, focusing on patient access, review processes, safety monitoring, ethical safeguards, and lessons from Japan's comparable framework.

Fondazione Italiana Linfomi - ETS

This is an observational, multicenter, prospective cohort study including patients treated with CAR-T in Italian centers. Patients eligible for enrollment in the study will be consecutively included in Italian FIL centers. A longitudinal survey will be carried out by collecting patients' data before starting CAR-T (T0) and after 6 (T1), 12 (T2) and 24 (T3) months after CAR-T infusion. Status: NOT_YET_RECRUITING Conditions: Diffuse Large B Cell Lymphoma (DLBCL); High Grade B Cell Lymphoma; Primary Mediastinal B-cell Lymphoma (PMBCL) Interventions: Chimeric Antigen Receptor T-cells (CAR-T) therapy

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

This study is a single arm, open label, dose exploring clinical trial to evaluate the safety, efficacy, cellular metabolic dynamics, and pharmacodynamics of ct1190b cells in relapsed / refractory B-cell acute lymphoblastic leukemia. Phase: EARLY_PHASE1 Status: RECRUITING Conditions: ALL (Acute B-Lymphoblastic Leukemia) Interventions: CT1190B cell injection

HeartWorks, Inc.

The goal of this clinical trial is to test the safety of lab-grown heart cells made from stem cells in subjects with congenital heart disease. The main questions it aims to answer are: * Is this product safe to deliver to humans * Is the conduct of this trial feasible Participants will be asked to: * Agree to testing and monitoring before and after product administration * Receive investigational product * Agree to lifelong follow-up Researchers will compare subjects from the same pool to see if there is a difference between treated and untreated subjects. Phase: PHASE1 Status: RECRUITING Conditions: Univentricular Heart; Congenital Heart Disease; Heart Failure NYHA Class III; Heart Failure NYHA Class IV Interventions: iPSC-CL

Janssen Research & Development, LLC

The purpose of this study is to compare the efficacy of Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel (cilta-cel) versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance in newly diagnosed multiple myeloma participants for whom ASCT is not planned as initial therapy in terms of Progression Free Survival (PFS). Phase: PHASE3 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple Myeloma Interventions: Bortezomib; Dexamethasone; Lenalidomide; Cilta-cel; Cyclophosphamide; Fludarabine

Prokidney

The purpose of this study is to assess the safety, efficacy, and durability of up to two Renal Autologous Cell Therapy (REACT) / rilparencel injections delivered percutaneously into biopsied and non-biopsied contralateral kidneys on renal function progression in two different cohorts of subjects with Type1 Diabetes Mellitus (T1DM) or Type2 Diabetes Mellitus(T2DM) and Chronic Kidney Disease (CKD). Phase: PHASE2 Status: COMPLETED Conditions: Chronic Kidney Diseases; Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus Interventions: Renal Autologous Cell Therapy (REACT)

Shane W English, Dean A Fergusson, Manoj Mathew Lalu et al.

The ability of immunomodulatory mesenchymal stromal cells (MSCs) to improve COVID-19-associated acute respiratory distress syndrome (ARDS) in clinical trials is uncertain. We assessed whether freshly cultured umbilical cord (UC)-derived MSCs improved outcomes in patients with severe COVID-19 ARDS. We enrolled 37 patients with severe COVID-19 ARDS: 15 in the phase 1 dose escalation and open label extension studies (NCT04400032), and 22 patients in the phase 2b randomized clinical trial (NCT04865107). Delivery of up to 270 &#xd7; 106 MSCs in three divided daily doses was well tolerated and resulted in qualitative improvement in all clinical outcomes. Furthermore, MSCs resulted in resolution of lymphopenia, consistent with an important immunomodulatory effect, with significant improvement in patient reported quality-of-life measures (SF-36) at 6 months pointing to possible durable clinical effects. These findings suggest a potential benefit of freshly cultured, UC-MSCs in severe COVID-19 ARDS, associated with biological evidence of favorable immunomodulatory activity.

Xu Wu, Chunsheng Wen, Chaonan Zhu et al.

The maintenance of human embryonic stem cell (hESC) self-renewal and pluripotency is governed by distinct signaling pathways, yet endogenous pluripotency-supporting pathways remain understudied despite extensive exogenous signaling research. Here, we identify a previously unrecognized role of endogenous VEGF signaling in sustaining primed hESC pluripotency. VEGF signaling is robustly activated in primed hESCs, quiescent in na&#xef;ve cells, and inactivated upon differentiation. Strikingly, targeted VEGFR inhibition (pharmacological, soluble decoy receptors [sFLT1/sKDR], or CRISPR-mediated VEGFR1/2 knockout) in primed hESCs disrupts self-renewal and induces trophoblast-like differentiation. Mechanistically, VEGFR inhibition activates the BMP pathway and down-regulates NANOG, which directly binds and represses select BMP components and trophoblast lineage-specific genes. Functionally, BMP inhibition partially and NANOG overexpression substantially rescue the phenotype induced by VEGF signaling ablation. Collectively, our work uncovers a pivotal VEGF-dependent network maintaining primed pluripotency, providing valuable insights into integrated pluripotency and lineage regulation by signaling cascades and transcription factors.

Ranabir Chakraborty, Francesca Palese, Philippa Samella et al.

Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of &#x3b1;-Synuclein (&#x3b1;-Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following &#x3b1;-Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon &#x3b1;-Syn exposure, resulting in compromised aggregate clearance. Such a response to &#x3b1;-Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of &#x3b1;-Syn from neuronal cells to microglia. Microglia co-cultured with &#x3b1;-Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing &#x3b1;-Syn aggregates to microglia.

Vera Skafar, Izadora de Souza, Biplab Ghosh et al.

Abstract Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR–Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B 2 ) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1–antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell’s antioxidant capacity.

Yutong Liu, Wenxin Zhang, Jing Cai et al.

Erythropoiesis, the process of red blood cell production, is highly dependent on iron uptake via transferrin and its receptor, transferrin receptor 1 (TfR1), but the mechanisms governing the proper recycling of TfR1 in relation to cellular iron demands remain elusive. Here, we identify human TMEM187, a Golgi transmembrane protein of unknown function, as a novel negative regulator of erythropoiesis. Lack of TMEM187 in a cell model initiates erythropoiesis without the normal induction protocol and accelerates iron uptake. Following the induction protocol, TMEM187 ablation leads to premature erythroid maturation, resulting in early phosphatidylserine ectopia and cell membrane fragility, hallmarks of cellular senescence that renders the cells susceptible to macrophage recognition and phagocytosis. In zebrafish embryos, tmem187 deletion leads to enhanced early erythropoiesis, although the phenotype is later compensated, whereas hematopoietic stem-cell expression of human TMEM187 in mice, which lack endogenously a homologous gene, resulted in compromised erythropoiesis and moderate anemia. Mechanistically, we demonstrate that TMEM187 interacts with RAB11 to restrain endosomal recycling, interfering with RAB11-GRAB association that activates RAB11. Consequently, TMEM187 modulates TfR1 recycling to the cell membrane to fine-tune iron uptake efficiency for erythropoiesis. Our findings reveal a novel modulatory pathway in which TMEM187 plays a crucial role in regulating erythroid differentiation, maturation, and senescence, providing a previously unexplored perspective of TMEM187's physiological function.

Amanda Gonz&#xe1;lez-Blanco, Adri&#xe1;n Acu&#xf1;a-Higaki, David Boettger et al.

Mosaic variegated aneuploidy (MVA), a rare human congenital disorder that causes microcephaly, is characterized by extensive abnormalities in chromosome number and results from mutations in genes involved in accurate mitotic chromosome segregation. To characterize the cellular mechanisms underlying this disease, here we generated a Drosophila model of microcephaly caused by the depletion of a single spindle assembly checkpoint (SAC) gene in the neural stem cell (NSC) compartment. We present evidence that loss of stemness - compromised identity and proliferative capacity of NSCs- plays an important role in MVA and results in a reduced number of neurons and glial cells. We show that loss of stemness arises from the accumulation over time of an unbalanced number of gains and losses of more than one chromosome, rather than a direct consequence of chromosomal instability-induced DNA damage or the production of simple aneuploidies. We unravel a contribution of proteostasis failure and mitochondrial dysfunction to the negative impact of complex aneuploidies on stemness, a highly energy demanding cellular state. We identify overexpression of Radical Oxygen Species scavengers, mitochondria chaperones and apoptosis inhibition as genetic interventions capable of dampening the deleterious effects of aneuploidy on brain size.

University of Florida

This is a phase I study to assess the safety and feasibility of IL-8 receptor modified patient-derived activated CD70 CAR T cell therapy in CD70+ pediatric high-grade glioma Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: High-grade Glioma Interventions: Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells

Wanying Jia, Hanlei Yan, Jingjing Huang et al.

Hirschsprung disease (HSCR) is a congenital condition featuring aganglionosis in the distal colon, causing functional obstruction. While EGF and bFGF are well-characterized neurogenic factors, the precise mechanistic role of GDNF in modulating enteric glial cell plasticity remains incompletely understood.

Ruicong Wang, Hongda Li, Jianfeng Wu et al.

University of California, Los Angeles

This clinical trial is being conducted to help liver transplant recipients safely discontinue toxic immunosuppressive drugs years after surgery. Lifelong use of these drugs is the current standard, but they come with life-threatening side effects. UCLA has pioneered this "Delayed Tolerance" approach, achieving success in numerous kidney recipients now living drug-free. The process uses a conditioning regimen followed by donor stem cell infusion to retrain the immune system to accept the liver as "self." Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Liver Transplantation; Immune Tolerance; Immune Tolerance/Drug Effects; Graft Survival; Hematopoietic Stem Cell; Chimerism; Immunosuppression After Liver Transplantation; Immunosuppression Disorders; End Stage Liver Disease Interventions: Donor Hematopoietic Stem and Progenitor Cell Infusion

Hitomi Hosoya, Armando N. Bastidas Torres, Sebastian Fernandez-Pol et al.

Abstract Chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative treatment for hematological malignancies, yet its potential to drive lymphomagenesis poses significant clinical concerns. In this study, we investigated the mechanisms underlying CAR T-cell–associated lymphomagenesis in the gastrointestinal (GI) tract on a single case, focusing specifically on the role of integrin α4β7 expression and a predisposing somatic SH2B3 mutation. We observed oligoclonal CAR T cells homing to, and clonally expanding in, the GI tract, with the dominant expanded clone harboring both a pathogenic SH2B3 mutation and a CAR transgene integration within a TFCP2 locus. The clonal CAR T cells subsequently transitioned beyond the GI tract into the peripheral blood, suggesting a potential pathway for systemic dissemination. We found clinical, histological, and molecular evidence demonstrating the efficacy of cyclosporine in reducing the expanded malignant clone and achieving durable clinical remission for more than a year. Our findings highlight the complex interplay between CAR T-cell therapy, preexisting genetic vulnerabilities, and the GI microenvironment, emphasizing the need for vigilant monitoring and tailored therapeutic strategies to address the risks associated with CAR T-cell lymphomagenesis.

Masaki Yagi, Konrad Hochedlinger

Meritxell Huch

Meritxell Huch spoke with Cell Reports about her scientific journey, mentorship philosophy, and lab culture as well as her research on human liver regeneration. She discussed refined liver organoid models capturing cholangiocyte heterogeneity and cellular plasticity and shared perspectives on challenges in organoid research and modern science.

Beijing Tongren Hospital

CAR-T cell therapy targeting CD19 has been shown to be effective in heavily-pretreated B-cell ALL or NHL, but relapses post-CAR-T are common, and CD19 antigen loss is one of the reasons. Thus, the investigators supposed that CD19/CD22 bispecific CAR-T cell therapy would be more effective and less relapses would occur in B- NHL. In this prospective phase 2 clinical trial, the investigators aim to explore the efficacy and safety of CD19/CD22 bispecific CAR-T cell therapy in relapsed/refractory Large B cell lymphoma. Phase: PHASE2 Status: RECRUITING Conditions: Large B-Cell Lymphoma (LBCL) Interventions: CD19/CD22 bispecific CAR-T cells

Johanna Friederike Steffen, Lina Widerspick, Stephanie Jansen et al.

West Nile virus (WNV), an arbovirus of emerging global interest, can cause neuroinvasive disease in humans. Currently, no protective vaccine or specific treatment is available for human WNV encephalitis. The virus induces neuronal cell death, while astrocytes and microglia cells are suspected to contribute to WNV pathology. Hence, understanding their role is crucial for future treatment approaches. In this study, we establish a WNV encephalitis model using human cerebral organoids, generated with male iPSCs. Infection results in heterogeneous kinetics with an early strong replication potentially leading to viral clearance, while a late peak was associated with more long-term infection. Viral foci are seen in cortical-like areas, rich in neurons and astrocytes, however void of microglia. Pro-inflammatory cytokines (IL-6, TNF-&#x3b1;, IL-18), chemokines (CXCL10, CCL17, CX3CL1, CCL2) and biomarkers (IL-1RA, sTREM-1, sRAGE, BDNF) are increasingly released. Conclusively, human cerebral organoids make suitable WNV encephalitis models with valuable properties to study acute and long-term infection.

Min Lu, M. Babu Mia, Lijuan Xia et al.

Abstract Cancer develops through the interactions between cancer stem cells and components of the tumor microenvironment (TME). To model in vivo cancer stem cell–TME interactions and elucidate their functional consequences, we focused on myelofibrosis (MF), a stem cell–driven myeloproliferative neoplasm. We cocultured MF hematopoietic stem and progenitor cells (HSPCs) with normal donor endothelial cells (ECs) and mesenchymal stromal cells (MSCs) to investigate the consequences of interactions between malignant MF HSPCs and nonmalignant microenvironmental cells. This tricultivation system proved to be a simple and reproducible platform, which promoted malignant clone dominance and the persistence of MF HSPCs that recapitulate the MF phenotype upon transplantation into immunodeficient mice, including splenomegaly and marrow fibrosis. Transcriptional profiling revealed extensive reprogramming of not only the cocultured MF HSPCs, but also MSCs and ECs. Although numerous disease-relevant pathways were upregulated, the proinflammatory response stood out as a key consequence of MF HSPC–TME interactions. We validated these findings through quantitation of proinflammatory transcript upregulation and cytokine production. This human multicellular model system has proven useful in demonstrating the multidirectional interactions of MF HSPCs with TME cells that are essential for sustaining fully functional MF stem cells.

Giada Rossignoli, Michael Oberhuemer, Ida Sophie Brun et al.

Abstract Naive human pluripotent stem cells (hPSCs) represent a pre-implantation epiblast state able to efficiently differentiate into embryonic and extraembryonic pre-implantation lineages and to self-organise in vitro into blastocyst-like structures called blastoids. Naive hPSC maintenance routinely relies on co-culture with mouse embryonic fibroblast (MEFs) as feeder cells, a method prone to variability and analytical confounders. Here, we describe a feeder-free culture system based on serum coating that supports long-term maintenance of naive hPSCs. Across five laboratories, 30 serum batches were evaluated for the expansion of eight naive hPSCs lines for up to 25 passages. Mass spectrometry analysis identified fibronectin and collagens as extracellular matrix proteins consistently present in serum coating. Cells cultured on serum coating displayed growth kinetics, clonogenic capacity, mutation rates, and global gene expression profiles comparable to MEF-based cultures. Importantly, serum-cultured naive hPSCs efficiently underwent germ layer specification, retained trophectoderm competence, and generated blastoids with efficiency similar to MEF-based cultures. Collectively, serum coating provides a scalable, cost-effective, and robust alternative to feeder-based systems, preserving genomic stability and developmental potential while eliminating MEF-associated disadvantages and variability. This platform facilitates large-scale applications of naive hPSCs and enables more reproducible mechanistic studies.

AvenCell Therapeutics, Inc.

This study is testing Allo-QuadCAR01-T, a new off-the-shelf CAR-T therapy for people with hard-to-treat B-cell cancers. Unlike current CAR-T treatments that use a patient's own cells, this therapy uses donor cells that are ready to use, which can save time and reduce costs. It targets two proteins, CD19 and CD20, to lower the chance of relapse and uses gene editing to make it safer. The trial has three parts: first to find a safe dose, then to confirm it, and finally to test how well it works in patients with diffuse large B-cell lymphoma (DLBCL). Patients will get one infusion after chemotherapy to prepare their body. The main goal is to check safety and see how many patients have a complete response by Week 13. About 160 patients will take part, and researchers will follow them for up to 15 years. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Lymphoma Diffuse Large B-cell; Leukemia and Lymphoma; Leukemia Relapse; Lymphoma Receiving CAR-T Therapy Interventions: Cyclophosphamide (Non-IMP, Lymphodepletion); Fludarabine (Non-IMP, Lymphodepletion); Allo-QuadCAR01-T

Haukeland University Hospital

The primary objective of the study is to investigate neuroregenerative efficacy (proof of concept) of intrathecal treatment with autologous MSCs as measured by neurophysiological parameters in patients with progressive MS. Secondary objectives are to assess neuroregenerative efficacy as measured by other neurophysiological parameters as well as clinical, opthalmological and MRI modalities, and to assess safety of the treatment procedure. Phase: PHASE1, PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple Sclerosis; Progressive Multiple Sclerosis Interventions: MSCs; Saline

Fred Hutchinson Cancer Center

This phase II clinical trial studies how well treosulfan, thiotepa, fludarabine, and rabbit anti-thymocyte globulin (rATG) before donor stem cell transplantation works in treating patients with nonmalignant (non-cancerous) diseases. Hematopoietic cell transplantation has been shown to be curative for many patients with nonmalignant (non-cancerous) diseases such as primary immunodeficiency disorders, immune dysregulatory disorders, hemophagocytic lymphohistiocytosis, bone marrow failure syndromes, and hemoglobinopathies. Powerful chemotherapy drugs are often used to condition the patient before infusion of the new healthy donor cells. The purpose of the conditioning therapy is to destroy the patient's abnormal bone marrow which doesn't work properly in order to make way for the new healthy donor cells which functions normally. Although effective in curing the patient's disease, many hematopoietic cell transplantation regimens use intensive chemotherapy which can be quite toxic, have significant side effects, and can potentially be life-threatening. Investigators are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan, thiotepa, and fludarabine phosphate) results in new blood-forming cells (engraftment) of the new donor cells without increased toxicities in patients with nonmalignant (non-cancerous) diseases. Phase: PHASE2 Status: RECRUITING Conditions: Non-Neoplastic Hematopoietic and Lymphoid Cell Disorder Interventions: Thiotepa; Treosulfan; Fludarabine Phosphate; Rabbit Anti-Thymocyte Globulin; Allogeneic Hematopoietic Stem Cell Transplantation; Bone Marrow Biopsy; Bone Marrow Aspiration; Magnetic Resonance Imaging; Biospecimen Collection

AstraZeneca

This is a randomised, multicentre, controlled, open-label, Phase III global study comparing the efficacy and safety of AZD0120 versus standard regimens (DKd \[daratumumab, carfilzomib, and dexamethasone\], DPd \[daratumumab, pomalidomide, and dexamethasone\], PVd \[pomalidomide, bortezomib and dexamethasone\], or Kd \[carfilzomib and dexamethasone\]) in participants with RRMM. Phase: PHASE3 Status: RECRUITING Conditions: Relapsed Refractory Multiple Myeloma Interventions: AZD0120; Daratumumab; Carfilzomib; Dexamethasone; Bortezomib; Pomalidomide

National Cancer Institute (NCI)

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses. Objective: To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL. Eligibility: People aged 3 to 39 with ALL or related B-cell lymphoma that has not been cured by standard therapy. Design: Participants will be screened. This will include: Physical exam Blood and urine tests Tests of their lung and heart function Imaging scans Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone. Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord. Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells. Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment. Participants will be admitted to the hospital. Their own modified T cells will be returned to their body. Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years.... Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B-NHL; B-Non Hodgkin Lymphoma; Acute Lymphocytic Leukemia; Acute Lymphoblastic Leukemia; B-precursor ALL; B-All; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, B Cell; B-Cell Lymphoma; B-Cell Leukemia; Acute Lymphoid Leukemia Interventions: CD19/CD22-CAR-transduced T cells; cyclophosphamide; fludarabine

Yi Zhang

This study was a prospective, multicenter, randomized controlled clinical study planned to recruit 266 hematological patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT), who were randomly divided into two groups according to gender, type of transplantation, and type of primary disease. The control group was treated conventionally, and the experimental group increased moxibustion of Zhongji, Guanyuan and Qihai for 30 min qd starting on the first day after HSCT was performed until the 14th day after transplantation. Urine routine tests were performed at the time of admission, +1d, and +14d, and urine BK virus, JC virus, and adenovirus were tested at four time points, namely, +1d, +14 days, onset of hematuria symptoms, and remission of HC, respectively; routine urine tests were performed once every 7 days for all patients within 100days. For patients with Hemorrhagic cystitis (HC), daily severity grading, pain scoring, cystitis symptom scoring, use of antispasmodic and analgesic medications, and major TCM evidence were recorded with the aim of evaluating the efficacy of moxibustion in the prevention of HC in this patient population. Phase: NA Status: RECRUITING Conditions: Moxibustion; Hematopoietic Stem Cell Transplantation; Hemorrhagic Cystitis; Prevention Interventions: Moxibustion; Symptomatic treatment

Children's Hospital Medical Center, Cincinnati

The purpose of this research study is to learn more about the use of viral specific T-lymphocytes (VSTs) to prevent or treat viral infections that may happen after allogeneic stem cell transplant. Allogeneic means the stem cells come from another person. VSTs are cells specially designed to fight viral infections that may happen after a stem cell transplant (SCT). Stem cell transplant reduces the body's ability to fight infections. Viral infections are a common problem after transplant and can cause significant complications. Moreover, treatment of viral infections is expensive and time consuming, with families often administering prolonged treatments with intravenous anti-viral medications, or patients requiring prolonged admissions to the hospital. The medicines can also have side effects like damage to the kidneys or reduction in the blood counts, so in this study the investigators are trying to find a better way to treat these infections. Phase: PHASE2 Status: RECRUITING Conditions: Allogeneic Stell Cell Transplant; Viral Infection Interventions: Viral Specific T-cells (VSTs) Scheduled; Viral Specific T-cells (VSTs) Treatment

Mert Ersan

This study aims to evaluate the potential effects of mesenchymal stem cell-derived suspended exosome therapy on facial skin quality using objective imaging analysis. Thirty adult participants will receive intradermal exosome applications in three treatment sessions performed at one-month intervals. Facial skin analysis will be conducted using the VISIA imaging system before each treatment session and six months after the final treatment. The study will examine changes in multiple facial skin characteristics including wrinkles, pigmentation, skin texture, pores, UV spots, red areas, brown spots, and porphyrins to determine whether exosome therapy may improve overall facial skin quality. Phase: PHASE3 Status: NOT_YET_RECRUITING Conditions: Skin Aging; Facial Aging; Skin Quality Interventions: Mesenchymal Stem Cell-Derived Exosome

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

RATIONALE: MAGE-A4 is a cancer-testis antigen widely expressed in various mesenchymal tumors but absent in normal tissues, making it an ideal immunotherapeutic target. Given the limited effectiveness of conventional therapies in advanced mesenchymal tumors, this study seeks to explore a novel treatment approach by engineering autologous T cells with a high-affinity TCR specific for MAGE-A4. PUOPOSE: This exploratory clinical study will assess safety profiles, treatment tolerance, and preliminary antitumor activity in patients with advanced mesenchymal malignancies. Phase: PHASE1 Status: RECRUITING Conditions: Advanced Mesenchymal Malignancies Interventions: TCR-T cells targeting MAGE-A4

James A. C. Bertlin, Tekle Pauzaite, Qian Liang et al.

Abstract Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau ( VHL ) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL , and uncover that loss of Core Binding Factor β (CBF-β) causes cell death in VHL -null ccRCC cell lines and impairs tumour establishment and growth in vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL -null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-β. Mechanistically, CBF-β loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-β at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-β in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.

Annika Zink, Dao-Fu Dai, Annika Wittich et al.

Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS), causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS-patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase type 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical safety. Sildenafil corrects mitochondrial membrane potential defects, restores neurodevelopmental pathways, and normalizes calcium responses in LS brain organoids. In small and large mammalian models of LS, sildenafil extends lifespan and ameliorates disease phenotypes. Off-label treatment on an individual basis with sildenafil in six LS patients improves their motor function and resistance to metabolic crises. Collectively, the findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.

Su Hyeon Myeong, Na Kyung Lee, Na-Hee Lee et al.

Mesenchymal stem cells (MSCs) are often considered hypoimmunogenic. However, a transient fever observed after intracerebroventricular (ICV) administration in a clinical trial suggests an acute host response. This study examines the mechanisms underlying this reaction, with a focus on MSC migration and the role of matrix metalloproteinase-9 (MMP9).

OneChain Immunotherapeutics

First in humans, exploratory, open-label, single-arm, multicentre, non-competitive, dose escalation study to assess the safety and efficacy of CD1a-CAR T therapy in patients with relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LL) Phase: PHASE1 Status: RECRUITING Conditions: T-cell Acute Lymphoblastic Leukemia; Lymphoblastic T-Cell Lymphoma Interventions: CD1a-CAR T

National Institute of Allergy and Infectious Diseases (NIAID)

This is a Phase I/II non-randomized clinical trial of ex vivo hematopoietic stem cell (HSC) gene transfer treatment for X-linked severe combined immunodeficiency (XSCID, also known as SCID-X1) using a self-inactivating lentiviral vector incorporating additional features to improve safety and performance. The study will treat 35 patients with XSCID who are between 2 and 50 years of age and who have clinically significant impairment of immunity. Patients will receive a total busulfan dose of approximately 6 mg/kg/body weight (target busulfan Area Under Curve is 4500 min\*micromol/L/day) delivered as 3mg/kg body weight on day 1 and dose adjusted on day 2 (if busulfan AUC result is available) to achieve the target dose, to condition their bone marrow, and this will be followed by a single infusion of autologous transduced CD34+HSC. Patients will then be followed to evaluate engraftment, expansion, and function of gene corrected lymphocytes that arise from the transplant; to evaluate improvement in laboratory measures of immune function; to evaluate any clinical benefit that accrues from the treatment; and to evaluate the safety of this treatment. The primary endpoint of the study with respect to these outcomes will be at 2 years, though data relevant to these measures will be collected at intervals throughout the study and during the longer follow-up period of at least 15 years recommended by the Food and Drug Administration (FDA) Guidance "Long Term Follow-Up After Administration of Human Gene Therapy Products" https://www.fda.gov/media/113768/download for patients participating in gene transfer clinical trials. XSCID results from defects in the IL2RGgene encoding the common gamma chain (yc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. At birth XSCID patients generally lack or have a severe deficiency of T-lymphocytes and NK cells, while their B- lymphocytes are normal in number but are severely deficient in function, failing to make essential antibodies. The severe deficiency form of XSCID is fatal in infancy without intervention to restore some level of immune function. The best current therapy is a T-lymphocyte-depleted bone marrow transplant from an HLA tissue typing matched sibling, and with this type of donor it is not required to administer chemotherapy or radiation conditioning of the patient's marrow to achieve excellent engraftment and immune correction of an XSCID patient. However, the great majority of patients with XSCID lack a matched sibling donor, and in these patients the standard of care is to perform a transplant of T- lymphocyte depleted bone marrow from a parent. This type of transplant is called haploidentical because in general a parent will be only half- matched by HLA tissue typing to the affected child. Whether or not any conditioning is used, haploidentical transplant for XSCID has a significantly poorer prognosis than a matched sibling donor transplant. Following haploidentical transplant, XSCID patients are observed to achieve a wide range of partial immune reconstitution and that reconstitution can wane over time in some patients. That subset of XSCID patients who either fail to engraft, fail to achieve adequate immune reconstitution, or lose immune function over time suffer from recurrent viral, bacterial and fungal infections, problems with allo- or autoimmunity, impaired pulmonary function and/or significant growth failure. We propose to offer gene transfer treatment to XSCID patients\^3 \>= 2 years of age who have clinically significant defects of immunity despite prior haploidentical hematopoietic stem cell transplant, and who lack an HLA-matched sibling donor. Our current gene transfer treatment protocol can be regarded as a salvage/rescue protocol. Prior successful retroviral gene transfer treatment instead of bone marrow transplant (BMT) in Paris and London for 20 infants with XSCID has provided proof of principle for efficacy. However, a major safety concern is the occurrence of 5 cases of leukemia at 3-5 years after treatment triggered in part by vector insertional mutagenesis activation of LMO2 and other DNA regulatory genes by the strong enhancer present in the long-terminal repeat (LTR) of the Moloney Leukemia Virus (MLV)- based vector. Furthermore, previous studies of gene transfer treatment of older XSCID patients with MLV- based vectors demonstrated the additional problem of failure of adequate expansion of gene corrected T- lymphocytes to the very high levels seen in infants. To reduce or eliminate this leukemia risk, and possibly enhance performance sufficiently to achieve benefit in older XSCID patients, we have generated a lentivector with improved safety and performance features. We have generated a self-inactivating (SIN) lentiviral vector that is devoid of all viral transcription elements; that contains a short form of the human elongation factor 1a (EF1a) internal promoter to expres... Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: X-linked Severe Combined Immunodeficiency (XSCID) Interventions: Ex vivo culture and transduction of the patient's autologous CD34+ HSC with lentivirus vector VSV-G pseudotyped CL20- 4i-EF1alpha-hgammac-OPT vector; Busulfan; Palifermin

Manuel Ricardo Espinoza-Gutarra

The goal of this observational study is to learn about the incidence of Transplant Associated Thrombotich Microangiopathy (TA-TMA), which is a known but underreported complication of Allogeneic Stem Cell Transplant (SCT). The main question it aims to answer is: What is the incidence of TA-TMA in adults undergoing SCT? How does TA-TMA diagnosis impact survival and other outcomes? Patients undergoing SCT will be eligible for this study, which will consist of collection of biological samples and standard clinical follow up. Status: NOT_YET_RECRUITING Conditions: Transplant Associated Microangiopathy TAM; Transplant Complication

Zihan Yang, Guanlin Qu, Xiping Wang et al.

Peripheral nerve injuries (PNIs) present a persistent clinical challenge because of the intrinsically limited regenerative capacity of peripheral nerves. While dental pulp stem cells (DPSCs) exhibit significant neuroregenerative potential, their therapeutic efficacy is constrained by hostile microenvironments and inherent functional heterogeneity. Genetic modification may offer a promising strategy to enhance their therapeutic capabilities.

Mesoblast, Inc.

Protocol 603 is enrolling subjects with moderate-to-severe Crohn's disease who are intolerant to, or have previously failed therapy with, at least one steroid and at least one immunosuppressant and a biologic monoclonal anti-body to tumor necrosis factor alpha. The protocol investigates the safety and efficacy of using PROCHYMAL® adult human stem cells to induce remission. PROCHYMAL is delivered through a vein in the arm four times over two weeks, for approximately an hour each time. Phase: PHASE3 Status: COMPLETED Conditions: Crohn's Disease Interventions: Prochymal®; Placebo

Peng Zhang, Hongyu Zheng, Zhao Lin et al.

Handong Li, Wenyan Zhang, Ting Li et al.

Bone marrow hematopoietic stem and progenitor cells (HSPCs) sense immune activation and instruct systemic immunity. However, the alterations of HSPCs in autoimmune diseases, which are driven by an active immune response, and their impact on disease activity and progression are not clear. Neuromyelitis optica spectrum disorder (NMOSD) is a B cell–mediated autoimmune neurological disease characterized by pathogenic autoantibodies against aquaporin-4 (AQP4-IgG). We observed aberrant bone marrow granulopoiesis in samples from individuals with NMOSD, which was accompanied by B cell clonal expansion. Aberrant granulopoiesis was mediated by hyperactivated JAK-STAT signaling, leading to an increase in ISG15 + neutrophils that produced B cell–activating factor (BAFF). These BAFF-producing neutrophils were sufficient to drive maturation of antibody-secreting cells and autoantibody production in vitro. Aberrant granulopoiesis was also observed in individuals with NMOSD receiving B cell depletion therapy who experienced relapse; in contrast, belimumab, a monoclonal antibody against BAFF, reduced autoantibody titers and number of relapses. Thus, targeting the bone marrow niche may present a treatment strategy for NMOSD and perhaps other B cell–mediated autoimmune diseases.

Tong Pan, Grace Lin, Xuan Li et al.

Biallelic pathogenic variants in STRADA (STE20-related adaptor alpha), an upstream regulator of the mechanistic target of rapamycin (mTOR) pathway, result in megalencephaly, drug-resistant epilepsy, and severe intellectual disability. This study explores how mTOR pathway hyperactivity alters cell fate specification in dorsal and ventral forebrain development using STRADA knockout human stem cell-derived brain organoids. In both dorsal and ventral forebrain STRADA knockout organoids, neurogenesis is delayed, with a predilection for progenitor renewal, increased proliferation and an expanded outer radial glia population. Ventrally, interneuron subtypes shift to an increase in neuropeptide Y-expressing cells. Inhibition of the mTOR pathway with rapamycin rescues most phenotypes. When mTOR pathway variants are present in all cells of the developing brain, overproduction of interneurons and altered interneuron cell fate may underlie mechanisms of megalencephaly, epilepsy, and cognitive impairment. Our findings suggest that mTOR inhibition during fetal brain development could be a potential therapeutic strategy in STRADA deficiency.

National Cancer Institute (NCI)

Background: * Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure that transplants bone marrow cells (stem cells) from a matching donor into a recipient in order to allow the donor stem cells to produce cells that will attack the recipient s cancer cells. AlloHSCT is performed when chemotherapy, immunotherapy, or radiation therapy do not adequately control cancer growth. However, cancers that are not controlled by alloHSCT frequently become resistant to other standard treatment options. * The outcomes of alloHSCT might be improved if certain kinds of white blood cells (T cells) could be manipulated so that they generate a more potent effect against the cancer cells. This effect can be augmented by genetically engineering donor T cells to specifically recognize cancerous cells in order to attack them. For this purpose, researchers are studying a specific kind of genetically engineered T cell known as the anti-CD19-CAR-transduced T cell. More research is needed to determine if this T cell will be an effective treatment for certain kinds of B cell cancer (such as non-Hodgkin s lymphoma and chronic lymphocytic leukemia) that has not been controlled with alloHSCT. Objectives: \- To assess the safety and effectiveness of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell cancer that has not responded to alloHSCT. Eligibility: * Individuals between 18 and 75 years of age who have received allogeneic hematopoietic stem cell transplantation for a B cell cancer, but whose cancer has either not responded to or recurred after the transplant. * Recipients must have the same stem cell donor from their previous procedure. Design: * Before the start of the study, all participants will be screened with a medical history and blood tests. Recipients will have tumor imaging scans, additional blood tests, and other tests as directed by the study doctors. * Donor participants will undergo apheresis to provide white blood cells for researchers to use in the treatment. * Recipients will have dose escalation to determine the most effective yet safe dose of anti-CD19 T cells. There will be six dose levels of anti-CD19 T cells. The first patients enrolled will have the smallest dose, and the dose will be increased when a level has been determined to be safe. . * Recipients will be hospitalized for at least 9 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 2, 4, 8, and 12 weeks after the infusion. * Additional scans and frequent blood tests will be required for the first 3 months after the infusion, followed by less frequent visits over time. * Recipients will be followed for a maximum of 15 years after receiving the infusion. Phase: PHASE1 Status: COMPLETED Conditions: Leukemia, B-cell; Lymphoma, Hodgkins; Lymphoma, Non-hodgkins; Lymphoma, B-Cell Interventions: Allogeneic stem cell transplant; Anti-CD19-chimeric-antigen-receptor-transduced T cells; Leukapheresis

Benedikt Strunz, Martin A Ivarsson, Dan Sun et al.

Maintenance of tissue-specific immunity is important for immunological fitness, but its establishment has been difficult to assess in humans. Here, we investigated reconstitution of the human uterine immune system by studying women who underwent uterus solid organ transplantation or hematopoietic stem cell transplantation (HSCT). Through single-cell identification based on single-nucleotide polymorphisms and disparate human leukocyte antigen expression using single-cell RNA sequencing or high-parameter flow cytometry, donor versus recipient cell origin was determined, and we examined the gene expression states, surface marker profiles, and spatial organization of these cells in the endometrium. Endometrial immune cell reconstitution occurred after both uterus transplant and HSCT at the transcriptomic, phenotypic, and spatial levels. Reconstitution involved restoration of all major immune lineages with frequencies comparable to those of healthy controls, with preservation of canonical endometrial immune architecture. Recipient-derived immune cells replaced donor immune cells after uterus transplant, whereas HSCT resulted in near-complete donor-derived immune reconstitution, including formation of tissue-resident lymphocytes. This occurred despite tacrolimus-induced, calcineurin-mediated inhibition of the nuclear factor of activated T cells (NFAT) pathway, which affected de novo induction of tissue-residency features in vitro. In one patient, immune cells of male origin reconstituted the endometrium after HSCT. Collectively, these data provide insights into tissue immune system persistence and reconstitution capabilities in the uterus, an organ that undergoes continuous regeneration.

Mesoblast, Inc.

The objective of the present study is to establish the safety and efficacy of Prochymal® following first acute myocardial infarction. Phase: PHASE2 Status: COMPLETED Conditions: Myocardial Infarction Interventions: Prochymal®; Placebo

Mesoblast, Inc.

Protocol 610 is enrolling subjects who successfully achieved clinical benefit (reduction in Crohn's Disease Activity Index (CDAI) of at least 100 points) in Protocol 603. Protocol 610 is evaluating the length of initial effect of PROCHYMAL® adult human mesenchymal stem cells and the ability of these cells to successfully re-induce clinical benefit. Phase: PHASE3 Status: COMPLETED Conditions: Crohn's Disease Interventions: Placebo; PROCHYMAL adult human mesenchymal stem cells

Mesoblast, Inc.

To provide open-label re-treatment with PROCHYMAL to participants enrolled in companion Protocol 603 to evaluate the safety in participants with active Crohn's disease who are resistant to standard Crohn's disease therapies. Phase: PHASE3 Status: COMPLETED Conditions: Crohn's Disease Interventions: Prochymal®

National Cancer Institute (NCI)

This phase II trial compares iberdomide maintenance therapy to disease monitoring for improving survival in patients who have received idecabtagene vicleucel (a type of chimeric antigen receptor T-cell \[CAR-T\] therapy) for multiple myeloma. The usual approach after treatment with idecabtagene vicleucel is to monitor the multiple myeloma without giving myeloma medications. There is currently no medication approved specifically for use after idecabtagene vicleucel treatment. Upon administration, iberdomide modifies the immune system and activates immune cells called T-cells, which could enhance the effectiveness of idecabtagene vicleucel. Iberdomide may keep multiple myeloma under control for longer than the usual approach (disease monitoring) after idecabtagene vicleucel, and may help multiple myeloma patients live longer. Phase: PHASE2 Status: RECRUITING Conditions: Multiple Myeloma Interventions: Biospecimen Collection; Bone Marrow Aspiration; Bone Marrow Biopsy; Computed Tomography; Iberdomide; Magnetic Resonance Imaging; Patient Monitoring; Positron Emission Tomography; Skeletal Survey X-Ray

Mesoblast, Inc.

The objective of the present study is to establish the safety and efficacy of multiple administrations of Prochymal™(ex-vivo cultured human adult mesenchymal stem cells) in participants with moderate to severe chronic obstructive pulmonary disease (COPD). Phase: PHASE2 Status: COMPLETED Conditions: Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Chronic Bronchitis Interventions: Prochymal™; Placebo

Biocells Medical

This study investigates the safety and efficacy of autologous stem cell therapy in patients with Multiple System Atrophy (MSA), a rare and progressive neurodegenerative disorder characterized by autonomic failure, parkinsonism, and cerebellar ataxia. The trial will evaluate functional outcomes, motor performance, and quality of life compared to placebo/controlled group. Phase: PHASE2 Status: NOT_YET_RECRUITING Conditions: MSA - Multiple System Atrophy; MSA Interventions: MSCs; Placebo

HONYA Medical Co Ltd

This trial is a Phase II, multicenter clinical study. The purpose of this trial is to evaluate the safety and efficacy of MiSaver, a cellular therapy product, in patients who have experienced an acute myocardial infarction (AMI). Specifically, the study aims to assess the improvement in left ventricular function of the heart following the administration of MiSaver, as well as to determine the safety of using stem cell therapy in these patients. This trial will employ a single-blind design (subject-blinded), meaning that the participants will not be aware of whether they are receiving MiSaver or standard treatment, while the researchers will have this information. This design helps ensure transparency and adherence to ethical standards while also providing valuable clinical insights. By utilizing randomization, we can enhance the reliability and comparability of the study results. A portion of the participants will receive MiSaver, while the others will undergo standard treatment. This allows for a direct comparison of the two therapeutic approaches to determine their respective efficacy. The primary objective of this trial is to evaluate the safety and efficacy of MiSaver, in the treatment of patients with acute myocardial infarction (AMI). To achieve this, we will collect comprehensive participant data, including assessments of cardiac function, records of cardiac events, and quality-of-life surveys. By analyzing these data, we aim to gain a deeper understanding of the benefits and limitations of this treatment approach. Phase: PHASE2 Status: NOT_YET_RECRUITING Conditions: Acute Myocardial Infarction (AMI) Interventions: Cord Blood Nucleated cells

Kangfu Chen, Wenhan Wang, Amber Lennon et al.

Lipid nanoparticles (LNPs) play a critical role in the delivery of therapeutic messenger RNA (mRNA). Despite extensive efforts to optimize lipid formulations for in vivo delivery, efficacy of mRNA by LNPs remains suboptimal in many organs. Here, we demonstrate that LNP delivery efficacy is influenced by cellular metabolism, with the physiologic metabolome imposing constraints on mRNA expression from LNPs. Using an in vitro system, we found that simulated physiologic metabolic conditions led to the down-regulation of certain amino acid metabolic programs. Supplementation with an optimized formulation of methionine, arginine, and serine as an amino acid supplement (AAS) enhanced the uptake of LNPs and the expression of delivered mRNA cargo in epithelial cells in vitro. Coadministration of AAS with LNPs led to a 5- to 20-fold improvement in mRNA expression across various cell types and lipid formulations in vitro by promoting clathrin-independent carrier–mediated endocytosis. Delivery of mRNA by LNPs coadministered with AAS by multiple routes enhanced in vivo mRNA expression in preclinical models. Delivery of mRNA encoding growth hormone by LNPs with coadministration of AAS improved the liver growth hormone expression and the therapeutic outcomes in a model of inflammatory liver damage. Delivery of gene editing materials by LNP and AAS through an intratracheal route increased lung-targeted in vivo gene editing efficiency compared with LNP alone. The addition of an optimized AAS as a codelivered agent with LNPs may provide a simple strategy to broadly improve the efficacy of mRNA-based cell and gene therapies.

Li Gao, Xiaowen Zhai, Ningling Wang et al.

Intensive chemotherapy is standard for AML but carries high risks of life-threatening complications, particularly in vulnerable patients. We aimed to compare the efficacy and safety of a low-dose chemotherapy (LDC) regimen for induction of AML. A randomized, multicenter, noninferiority trial was conducted in patients aged <18 years with AML. Patients received low-dose cytarabine, mitoxantrone or idarubicin, and G-CSF (LDC) or standard-dose induction chemotherapy (SDC) (cytarabine, daunomycin, and etoposide). All patients received post-remission consolidation with standard chemotherapy and/ or hematopoietic stem cell transplantation. The primary endpoint was to compare response rates between treatments. The secondary endpoints were to compare the outcomes, toxicity, and safety of the LDC and SDC regimens. The two treatment arms showed no significant differences in outcomes. Complete remission (CR/CRi) rates after induction were 95.1% and 95.3% in the LDC and SDC arms, respectively. Measurable residual disease < 0.1% after induction II was observed in 87.4% and 87.1% of patients in the LDC and SDC arms, respectively. Median time to neutrophil and platelet recovery was significantly shorter among patients receiving the LDC regimen. Patients in the LDC arm had a 4-year overall survival (OS) of 81.3% vs. 83.6% (P&#x2009;=&#x2009;.611) and a 4-year event-free survival (EFS) of 61.5% vs. 63.1% (P&#x2009;=&#x2009;.832). In conclusion, the LDC regimen was well tolerated and was associated with CR, EFS, and OS rates that were not inferior to those of patients treated with the SDC regimen. The trial was registered at Chinese Clinical Trial Registry (ChiCTR1800015883).

Kamau Therapeutics

This study is a first-in-human, single-arm, open-label Phase I/II study of nula-cel in approximately 15 participants, diagnosed with severe Sickle Cell Disease. The primary objective is to evaluate safety of the treatment in this patient population, as well as preliminary efficacy and pharmacodynamic data. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Sickle Cell Disease Interventions: nula-cel Drug Product

Peking University First Hospital

This is a single-arm, open-label clinical trial designed to assess the safety and therapeutic efficacy of iPSC-derived islet cell infusion in patients with diabetes mellitus. Phase: NA Status: NOT_YET_RECRUITING Conditions: Diabetes Mellitus Interventions: iPSC-derived islet cell

Guangmei Ran, Hongrui Jin, Qian Yang et al.

The rapidly growing diabetic population is at high risk of dental implant failure due to a disrupted peri-implant immune microenvironment. Mesenchymal stem cells-derived exosomes (MSC-Exos) have emerged as a potent nanotherapeutic platform to remodel this hostile niche. Their mechanisms involve reprogramming macrophage polarization to alleviate inflammation, delivering pro-angiogenic miRNAs to restore vascular-osteogenic coupling, and modulating neuro-immune crosstalk to reestablish homeostasis. Collectively, these actions break the vicious cycle of impaired healing. Furthermore, engineering strategies such as membrane modification, integration with biomaterials, and preconditioning of parent cells can enhance the targeting, stability, and controlled release of MSC-Exos, thereby improving osseointegration outcomes in diabetic models. These engineering innovations, which focus on precise delivery and controlled release, are as critical to therapeutic development as elucidating the underlying biological mechanisms. This review systematically delineates the mechanisms by which MSC-Exos recalibrate the diabetic bone immune niche to foster osseointegration and critically discusses the clinical translation prospects of engineered exosome-based therapies.

M.D. Anderson Cancer Center

The main goal of this clinical research study is to learn if Velcade ® (bortezomib) given with rituximab can help to control WM. This drug combination will allow researchers to collect your stem cells in case it is possible to transplant the stem cells as treatment if your WM gets worse. Researchers will also look at the safety and tolerability of this drug combination followed by treatment with other drug combinations. Phase: PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: Waldenstrom's Macroglobulinemia Interventions: Bortezomib; Rituximab; Valacyclovir

National Cancer Institute (NCI)

This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy works for treating children with newly diagnosed high-risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found on the surface of neuroblastoma cells, but is not present on many healthy or normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal the immune system to kill the tumor cells. This helps the cells of the immune system kill the cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy. Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a disease evaluation is completed to determine how well the treatment worked. If the tumor responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide. Patients with a good response to therapy move on to Consolidation therapy, when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells. Following, transplant, radiation therapy is given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of Induction. The final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given with isotretinoin, with the goal of maintaining the response achieved with the previous therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma. Phase: PHASE3 Status: RECRUITING Conditions: Ganglioneuroblastoma, Nodular; Neuroblastoma Interventions: Biospecimen Collection; Bone Marrow Aspiration; Bone Marrow Biopsy; Carboplatin; Cisplatin; Computed Tomography; Cyclophosphamide; Dinutuximab; Doxorubicin; Echocardiography Test; Etoposide; FDG-Positron Emission Tomography and Computed Tomography Scan; Hematopoietic Cell Transplantation; Irinotecan; Isotretinoin; Leukapheresis; Magnetic Resonance Imaging; Melphalan; Multigated Acquisition Scan; Radiation Therapy; Radionuclide Imaging; Survey Administration; Temozolomide; Thiotepa; Topotecan; Tumor Resection; Vincristine

Thomas Martin, MD

This phase Ib trial tests the safety, side effects and best dose of clustered regularly interspaced short palindromic repeats (CRISPR) delivered anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells (1XX BCMA CAR-T cells) in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Anti-BCMA CAR-T cell therapy is a type of treatment in which a person's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein, such as BCMA, on the patient's cancer cells is added to the T cells in the laboratory by a tool called clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. The special receptor is called a CAR. Large numbers of the CAR-T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving chemotherapy before CAR-T cells may decrease the number of lymphocytes (a type of white blood cells) in the blood and may help the 1XX BCMA CAR-T cells fight the cancer cells. Treatment with 1XX BCMA CAR-T cells may be safe, tolerable, and/or effective in treating patients with relapsed or refractory multiple myeloma (RRMM). Phase: PHASE1 Status: RECRUITING Conditions: Multiple Myeloma; Recurrent Multiple Myeloma; Refractory Multiple Myeloma Interventions: Leukapheresis; Cyclophosphamide; Chimeric Antigen Receptor T cells (CAR-T) Targeting BCMA; Quality of Life (QoL) Questionnaires; Bone Marrow Biopsy; Biospecimen Collection; Fludarabine; Radiographic imaging

Qi Liu, Guodong Liu, Dong Sun et al.

The issue of kidney disease represents a significant global health challenge. While current treatment options may provide symptomatic relief, they are limited by several factors. Consequently, there is a pressing need to create more effective therapeutic strategies. Mesenchymal stromal cell (MSCs) and their secretome have attracted considerable attention in the field of regenerative medicine owing to their multidirectional differentiation potential, immunomodulatory properties, and paracrine effects, which offer a promising solution to this challenge. However, direct transplantation of MSCs and their secretome faces problems such as low survival rate and unstable therapeutic effect in practical applications. These challenges have prompted researchers to explore strategies to enhance the therapeutic potential of MSCs and their secretory factors through pretreatment. This review summarizes the current research progress on pretreated MSCs and their secretome in the treatment of kidney diseases and discusses how various pretreatment approaches can enhance their therapeutic efficacy and clinical application in renal disorders, thereby providing insights for the future optimization and therapeutic use of MSCs.

Beijing GoBroad Hospital

This is a multi-center, open-label, non-randomized, two-arm, non-inferior trial. Patients with r/r B-ALL would be assigned to the CD19 CAR and CD22 CAR T-cell sequential infusion group (Sequential CAR, Arm-1) and the CD19 CAR T-cell infusion bridging to hematopoietic stem cell transplantation group (CAR+HSCT, Arm-2), according their own discretion. Patients would be also allowed to assigned to the CD19 CAR T-cell infusion without consolidation therapies group (Single CAR, additional placebo arm) according their own discretion. The primary objective is to prospectively evaluate and compare the efficacy of CD19 CAR and CD22 CAR T cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT in the treatment of r/r B-ALL. The primary endpoint is event-free survival of children and adolescent and young adult (AYA) with r/r B-ALL a treated with CD19 CAR and CD22 CAR T-cell sequential infusions and CD19 CAR T-cell infusion bridging to HSCT. A total number of 353 subjects will be enrolled. Phase: NA Status: RECRUITING Conditions: B-cell Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia, in Relapse; Refractory Acute Lymphoid Leukemia Interventions: CD19 CAR T-cell; CD22 CAR T cells; hematopoietic stem-cell transplantation

Yusuke Maruyama, Ken'ichiro Nogami, Norio Motohashi et al.

Muscle satellite cells are adult muscle stem cells indispensable for growth and regeneration of postnatal skeletal muscle. Notch plays a central role in maintenance of muscle satellite cells, but how Notch maintains the muscle stem cell pool is not fully understood. Previously, we reported that a prostaglandin E2 receptor, EP2, is upregulated by Notch signal and suppresses differentiation of human muscle progenitors. Here we examined the roles of EP2 in muscle satellite cells using a mouse Cre-LoxP conditional gene knockout system. Genetic inactivation of the EP2 gene (PTGER2) activated muscle satellite cells, caused their loss, and impaired muscle regeneration. These results indicate that EP2 is indispensable for maintenance of satellite cells. Ex vivo analysis using isolated myofibers showed that prostaglandin E2 (PGE2) delayed the activation of satellite cells via EP2. An extracellular signal-regulated kinase (ERK) 1/2 inhibitor blocked the activation of satellite cells on myofibers, and PGE2 attenuated the phosphorylation of ERK1/2 in muscle satellite cells. These results suggest that EP2 keeps the quiescence of satellite cells and maintains the satellite cell pool in part by inhibiting the ERK1/2 signaling pathway.

Melanie Senior, Ricardo Grieshaber-Bouyer

St. Jude Children's Research Hospital

The purpose of this study is to learn more about newer methods of transplanting blood cells donated by a partially matched family member to children with high-risk CD19 positive leukemia ALL. Primary Objective: \- To assess the safety and feasibility of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies. Secondary Objectives: * To estimate 1-year post-transplant overall survival, event-free survival, and GVHD-free relapse-free survival (GRFS). * To estimate cumulative incidence of engraftment, acute and chronic GVHD, and immune-related adverse events, including CRS and ICANS. Phase: PHASE1 Status: RECRUITING Conditions: Relapsed Pediatric ALL; Hematopoietic Cell Transplantation; Hematologic Malignancy Interventions: Anti-Thymocyte Globulin (Rabbit); Cyclophosphamide; Fludarabine; Thiotepa; Mesna; Melphalan; Filgrastim; CliniMACS System

National Cancer Institute (NCI)

Background: Acute lymphoblastic leukemia (ALL) is a type of blood cancer. Chimeric antigen receptor (CAR) therapy involves taking immune cells (T cells) from a person and modifying them to better target cancer cells. CAR T-cell therapy that targets a marker called CD19 has been show to can cure ALL in many children and adults. But in about 50% of patients, the ALL comes back within a year. Researchers want to find out if a second treatment with CAR T-cell therapy that targets a different marker, CD22, can keep the cancer away longer. Objective: To see if CD22 CAR T-cell therapy can keep ALL away longer. Eligibility: People aged 3 to 65 years who have no signs of cancer after CD19 CAR T-cell treatment for ALL. Design: Participants will be screened. They will have imaging scans and tests of their heart function. A sample of tissue (biopsy) will be collected from their bone marrow. They will have a fluid sample collected from the area around their spinal cord. Participants will undergo collection of their white blood cells (T cells) during a procedure called leukapheresis. Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. The cells will be altered in a lab to create CD22 CAR T-cell therapy. Participants will take drugs over 4 consecutive days to prepare their body for the CAR T-cell therapy; then they will receive their modified T cells through a tube inserted into a vein. Some people may need to stay in the hospital during treatment. Participants will have follow-up visits for 2 years. Phase: PHASE2 Status: NOT_YET_RECRUITING Conditions: Acute Lymphoblastic Leukemia; B-All Interventions: CD22 CAR-transduced T cells; Cyclophosphamide; Fludarabine

Beijing GoBroad Hospital

This study is a multi-center, open-label, non-randomised, single-arm phaseⅠclinical trial to explore the safety and efficacy of FL-33 CAR T therapy for refractory/relapsed acute myeloid leukaemia. The primary endpoints are incidence and type of dose limiting toxicity within 21 days of CAR T infusion; total number, incidence and severity of adverse events (AE) 30 days after CAR T infusion. The secondary endpoints are total number, incidence and severity of AEs 30 days to 2 years after CAR T infusion; objective response rate (ORR), complete response rate (CR) and complete response with incomplete haematological recovery (CRi) by dose group at 15, 30 and 90 Days after CAR T Infusion; duration of response (DOR), progression-free survival (PFS), overall survival (OS); pharmacokinetic characteristics. The trial will use BOIN12 design to explore the optimal biological dose (OBD) of FL-33 CAR T cells for refractory/relapsed acute myeloid leukaemia. FL-33 CAR T is set at two dose levels: 5\*10\^5 (±20%) CAR-T cells/kg for dose 1 (DL-1) and 1\*10\^6 (±20%) CAR-T cells/kg for dose 2 (DL-2), and after the optimal biological dose (OBD) is determined in the dose exploration phase, the dose expansion phase will expand the trial by 6-12 cases at the OBD, enrolling up to 21-27 cases. Enrolment of more than 21 cases can be reported for analysis and the trial will be stopped when enrolment reaches 27 cases.Additionally, an independent observation group was established, comprising two sequential cohorts: a minimum of 3 subjects were enrolled starting from the lowest dose level (DL-1). Phase: PHASE1 Status: RECRUITING Conditions: Refractory/Relapsed Acute Myeloid Leukaemia Interventions: autologous FL-33 CAR T therapy; prior-HSCT donor-derived FL-33 CAR T therapy; Newly matched donor-derived FL-33 CAR T therapy; FL33-03 CAR-T therapy

Sebastian Hernandez, Hunter E Schweiger, Isabel Cline et al.

The mouse cortex is a canonical model for studying how functional neural networks emerge, yet it remains unclear which topological features arise from intrinsic cellular organization versus sensory input. Mouse forebrain organoids provide a powerful system to investigate these intrinsic mechanisms. We generated dorsal (DF) and ventral (VF) forebrain organoids from mouse pluripotent stem cells and tracked their development using longitudinal electrophysiology. DF organoids showed progressively stronger network-wide correlations, while VF organoids developed more refined activity patterns with enhanced small-world topology and increased modular organization. Both organoid types form small-world networks, but their topological organization differs. These differences emerge without extrinsic inputs and correlate with Pvalb+ interneuron enrichment in VF organoids. Our findings demonstrate how cellular composition influences neural circuit self-organization, establishing mouse forebrain organoids as a tractable platform to study cortical network architecture.

Noah Tech, Corp.

This study aims to evaluate the efficacy of community-based early detection and targeted interventions, including stem cell therapy and wearable non-invasive brain-computer interface (BCI) devices, for Mild Cognitive Impairment (MCI) in adults aged 55 years and older residing in U.S. urban and suburban communities. Primary objectives include assessing improvements in MCI detection rates, cognitive outcomes, and progression delay compared to standard care. Phase: EARLY_PHASE1 Status: NOT_YET_RECRUITING Conditions: Mild Cognitive Impairment (MCI); Early Stages of Cognitive Decline; Alzheimer's Disease Dementia; Alzheimer's Disease Diagnosis; Alzheimer's Disease and Related Dementias; Parkinson's Disease; Parkinson's Disease (PD); Parkinson's Disease With Wearing-off Motor Fluctuations; Dementia (Diagnosis); Dementia MCI (Mild Cognitive Impairment) Interventions: Structured wellness care; Wearable brain-computer interface devices; Stem Cell Therapy - Experimental; Control - Placebo Comparator

Beijing GoBroad Hospital

A Clinical Study Exploring CT1190B in the treatment of patients with moderate to severe refractory systemic lupus erythematosus (SLE) or refractory/progressive systemic sclerosis (SSc) Phase: PHASE1 Status: RECRUITING Conditions: Systemic Lupus Erythematosus (SLE); Systemic Sclerosis (SSc) Interventions: CAR-T Therapy

M.D. Anderson Cancer Center

This is a phase I trial followed by a phase II randomized trial. The purpose of phase I study is the feasibility of treating patients with acute respiratory distress syndrome (ARDS) related to COVID-19 infection (COVID-19) with cord blood-derived mesenchymal stem cells (MSC). The purpose of the phase II trial is to compare the effect of MSC with standard of care in these patients. MSCs are a type of stem cells that can be taken from umbilical cord blood and grown into many different cell types that can be used to treat cancer and other diseases. The MSCs being used for infusion in this trial are collected from healthy, unrelated donors and are stored and grown in a laboratory. Giving MSC infusions may help control the symptoms of COVID-19 related ARDS. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: COVID-19 Infection; COVID-19-Associated Acute Respiratory Distress Syndrome; Hematopoietic and Lymphoid Cell Neoplasm; Malignant Solid Neoplasm; Symptomatic COVID-19 Infection Laboratory-Confirmed Interventions: Best Practice; Mesenchymal Stem Cell

Xuewen Duan, Yong Tan, Yunkai Zhang et al.

Stimulating endogenous cardiomyocyte proliferation holds great therapeutic promise for cardiac repair, but how chromatin remodeling governs this process remains poorly understood. RNA-binding motif 22 (RBM22) participates in the regulation of various biological contexts, whereas its role in cardiac regeneration and repair is largely unknown. Here, we identify RBM22 as a pivotal regulator of cardiomyocyte proliferation. Cardiomyocyte-specific deletion of Rbm22 impairs neonatal heart regeneration and exacerbates post-infarction ventricular remodeling in adult mice. Mechanistically, RBM22 selectively binds to the proximal promoters of key cell cycle genes (Cdk4, Ccna2, and Ccne1), where it cooperates with chromatin remodeler SMARCA4 to enhance transcriptional accessibility. Furthermore, RBM22 is essential for the gene-specific recruitment of RNA Polymerase II to these gene loci to drive transcription. AAV9-mediated delivery of Rbm22 promotes cardiomyocyte proliferation in vivo following cardiac damage and increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. Our findings establish RBM22 as a transcriptional and epigenetic regulator that overcomes cell-cycle barriers in cardiomyocytes, highlighting its therapeutic potential for cardiac injury.

Beijing GoBroad Hospital

This is a multi-center, open-label, non-randomized, phase 1/2 study of anti-CD5 CAR-T cell therapy in patients with CD5+ relapsed or refractory T-cell malignancies. A bayesian optimal interval (BOIN) 12 design will be used to explore the optimal biological dose (OBD) from starting dose level 1: 1×10\^6 (±20%) to dose level 2: 2×10\^6 (±20%) in three cohorts (autologous, previous-transplant-donor or newly matched donor-derived CD5 CAR T cells). If the manufactured cells are not sufficient to meet the preassigned standard dose criteria, patients will be given infusion at a low dose level of 5×10\^5 (±20%) /kg. The primary objective is to evaluate the safety and tolerability of CD5 CAR T cell therapy in subjects, determine the OBD and recommend phase 2 dose (RP2D) in phase 1, and evaluate the efficacy of CD5 CAR T cell therapy in phase 2. The primary endpoint is the type and incidence of dose-limiting toxicity (DLT) within 28 days, and the incidence and severity of adverse events (AEs) within 30 days after CD5 CAR T-cell infusion in phase 1, the best overall response (BOR) at 3 months (± 1 week) after CD5 CAR T-cell infusion in phase 2. A total number of 54 subjects will be enrolled. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: T-Cell Acute Lymphocytic Leukemia; Acute Lymphoblastic Leukemia, in Relapse; Refractory Acute Lymphoblastic Leukemia; T-cell Malignancies Interventions: Autologous CD5 CAR T-cells; Previous stem-cell transplantation (SCT) donor-derived CD5 CAR T-cells; Newly matched donor-derived CD5 CAR T-cells

Instituto de Investigacion Sanitaria INCLIVA

The goal of this clinical trial is to learn if two non-pharmacological strategies can help reduce neurotoxicity caused by CAR-T cell therapy in adult patients with hematologic cancer, both sexes, aged 18 to 80 years. The strategies are: * A structured physical activity program. * A combination of physical activity and nutritional recommendations. The main questions it aims to answer are: * Does physical activity help lower the risk or severity of neurotoxicity after CAR-T therapy? * Does combining physical activity with nutritional recommendations provide greater protection against neurotoxicity than physical activity alone? Researchers will compare two intervention groups with a control group (no intervention) to see which approach is most effective in reducing neurotoxicity and improving recovery. Participants will be randomly assigned to one of three groups using stratified randomization to ensure balanced clinical and demographic characteristics: * Group A: Structured physical activity program. * Group B: Structured physical activity program combined wuth nutritional recommendations. * Group C: No intervention; used to establish baseline patterns. Participants will be evaluated periodically by study professionals. Comprehensive records of symptoms, health measurements, and relevant lifestyle data will be maintained throughout the study. Phase: NA Status: RECRUITING Conditions: Hematologic Cancer Interventions: Physical activity; Physical activity and nutrition

Beijing GoBroad Hospital

The goal of this study is to evaluate the safety and efficacy of CD19 CAR T cells in the treatment of Systemic lupus erythematosus (SLE). Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: Systemic Lupus Erythematosus (SLE); Lupus Nephritis (LN) Interventions: CD19 CAR-T cells

Feng Li, Yuxing Hu, Yan Wang et al.

Although promising, chimeric antigen receptor T (CAR T) cell therapy for treating leukemias still faces the critical challenge of antigen modulation, which causes resistance. Building from our clinical insight that both diverse types of leukemia cells and corresponding CAR T cells strongly express CD71 (a ferritin receptor), we designed a ferritin aggregation cell engager (FACE) that can anchor to the CAR T cell surface, guide CAR T cells to face leukemia cells, and facilitate CAR recognition of cognate antigens. In vitro and in vivo experiments with diverse leukemia patient-derived cells and leukemia patient-derived xenograft models show that our FACE-CAR T cells succeed in enhancing therapeutic efficacy with good biosafety, lowering the antigen threshold for overcoming antigen modulation, and even loading chemodrugs in ferritin for combination therapy. This avidity engineering provides a neotype, facile, universal, and flexible approach for improving the efficacy of CAR T cell therapy for diverse refractory leukemias.

Healing Hope International

This prospective observational study evaluates the safety profile and patient-reported outcomes associated with MUSE (Multilineage-differentiating Stress-Enduring) stem cell therapy in individuals aged 6 to 75 with chronic traumatic brain injury (TBI). Participants independently elect to receive MUSE cell treatment through international clinical programs, and this study aims to capture real-world evidence on the potential therapeutic effects and risks of this emerging regenerative approach. The study does not administer any intervention. Instead, it follows participants who have received, or plan to receive, MUSE cell infusions outside the United States. Over a 12-month follow-up period, data will be collected on neurological functioning, quality of life, activities of daily living, and any reported adverse events or complications. Information will be gathered through remote interviews, structured digital surveys, and review of medical documentation when available. This research is sponsored by Healing Hope International and is intended to contribute to the ethical and responsible advancement of novel cell-based therapies by generating real-world evidence that may guide future clinical trial development and inform patient care practices. Status: NOT_YET_RECRUITING Conditions: Traumatic Brain Injury; Traumatic Brain Injury (TBI) Patients; Traumatic Brain Injury (TBI); Concussion, Initial Encounter; Traumatic Brain Injury (TBI); Concussion, Subsequent Encounter; Traumatic Brain Injury With Brief Loss of Consciousness; Traumatic Brain Injury With Persistent Cognitive Deficits Interventions: MUSE Stem Cell Therapy

Chulalongkorn University

A Phase 1b clinical trial to evaluate the safety and efficacy of BCMA-targeted CAR T-cell therapy in Thai patients with relapsed or refractory multiple myeloma. Phase: EARLY_PHASE1 Status: NOT_YET_RECRUITING Conditions: Relapsed/Refractory Multiple Myeloma (MM) Interventions: Chimeric Antigen Receptor T Cells (CAR-T)

Mayo Clinic

The purpose of this study is to determine the safety and efficacy of intrathecal treatment delivered to the cerebrospinal fluid (CSF) of mesenchymal stem cells in ALS patients every 3 months for a total of 4 injections over 12 months. Mesenchymal stem cells (MSCs) are a type of stem cell that can be grown into a number of different kinds of cells. In this study, MSCs will be taken from the subject's body fat and grown. CSF is the fluid surrounding the spine. The use of mesenchymal stem cells is considered investigational, which means it has not been approved by the Food and Drug Administration (FDA) for routine clinical use. However, the FDA has allowed the use of mesenchymal stem cells in this research study. Phase: PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: ALS; Amyotrophic Lateral Sclerosis Interventions: Autologous Adipose-derived Mesenchymal Stromal Cells

Jiawei Zhou, Yangyang Cao, Ziyan Sun et al.

Research on cartilage repair in the knee joint is crucial for treating knee arthritis or injuries. The application of mesenchymal stem cells (MSCs) for cartilage tissue regeneration represents a promising therapeutic approach. Among the critical aspects in cartilage formation, the enhancement of MSC chondrogenic differentiation stands as a pivotal challenge. WDR63 is a cytoplasmic dynein that plays a significant role in promoting stem cell differentiation and is closely associated with the cytoskeleton and energy metabolism processes. In the current study, our objective is to elucidate the phenotypic manifestations and mechanisms of WDR63 in relation to its chondrogenic differentiation function in MSCs.

Xuanwu Hospital, Beijing

This study is divided into two phases: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase is a single-center study, while the expansion cohort phase is a multicenter, prospective, randomized, double-blind, placebo-controlled study. Phase: PHASE1, PHASE2 Status: NOT_YET_RECRUITING Conditions: Mild to Moderate Alzheimer's Disease Interventions: Exosomes derived from umbilical cord mesenchymal stem cell for intranasal drop; A placebo of exosomes derived from umbilical cord mesenchymal stem cell for intranasal drop

Qiong Rong, Ling Ma, Mengting Wang et al.

Early vascularization is one of the limitations of periodontal tissue engineering (PTE) based on mesenchymal stem cells (MSCs). Directed differentiation of endothelial progenitor cells (EPCs) into endothelial cells facilitates the osteogenic effect of MSCs. Therefore, this study constructed EPCs/peripheral blood derived-MSCs (EPCs/PBMSCs) sheets and evaluated their repair value and potential molecular mechanisms in bone regeneration.

Hope Biosciences Research Foundation

This expanded access protocol is part of IND 32226 to evaluate efficacy and safety of multiple intravenous administrations of allogeneic HB-adMSCs for the treatment of Multiple System Atrophy for up to 7 adult patients who pass pre-screening and a completed screening. The subjects will receive 12 intravenous infusions of HB-adMSCs and 6 intrathecal injections of HB-adMSCs over the course of 44 weeks (1 infusion each month and 1 injection every other month). Status: TEMPORARILY_NOT_AVAILABLE Conditions: Multiple System Atrophy Interventions: HB-adMSCs - Hope Biosciences Adipose Derived Mesenchymal Stem Cells

National Institutes of Health Clinical Center (CC)

Background: People who receive an allogeneic hematopoietic stem cell transplant (HSCT) require long-term care at home afterwards. Their caregivers often experience high levels of stress, which can lead to symptoms such as depression, anxiety, poor sleep, fatigue, and difficulties with concentration and memory. Objective: To explore whether a nature-based immersive virtual reality (VR) program helps reduce stress in people who care for HSCT patients. Eligibility: People aged 18 and older who are primary caregivers of HSCT patients. Design: This is a two-phase study. Participants will be enrolled for 4 weeks. They will have 2 clinic visits. Participants will have a physical exam at the beginning of the study. They will be asked to provide a saliva sample in Phase 1, and saliva and blood samples in Phase 2. Participants will be given a VR headset. This is a device that looks like a pair of goggles worn over the eyes. They will be asked to wear the headset for 20 minutes per day. They will see 360 (Infinite) high-definition videos of nature and hear nature sounds. Participants will record the time they spend using the VR headset in a daily diary. They will take surveys with questions about any stress and symptoms they feel once a week. This will take up to 5 minutes. Participants will have a short regular follow-up visit by phone one week after starting their participation. At the end of the intervention study, participants will return for another physical exam. They will give saliva and/or blood samples again. Researchers will also look at the medical records of the HSCT patients; the HSCT patients must consent to this.... Phase: NA Status: RECRUITING Conditions: Neoplasm; Caregivers Interventions: Sham VR; Active VR

Beijing GoBroad Hospital

This is an investigator-initiated, single-arm, open-label, non-randomised phase I clinical study. The objective of this trial is to evaluate the safety, tolerability and pharmacokinetics of donor-derived CD19 CAR Therapy bridged Allo-HSCT and sequential donor-derived CD22 CAR Therapy for r/r B-ALL and to explore the efficacy of this therapy preliminarily. The primary endpoints are incidence and type of dose-limiting toxicity (DLT) within 28 days (i.e., 43 days after donor-derived CD19 CAR T-cell infusion) after donor-derived CD19 CAR T-cell therapy bridged allogeneic haematopoietic stem cell transplantation; total number, incidence and severity of adverse events from donor-derived CD19 CAR T cell infusion back to 30 days after donor-derived CD22 CAR T cell infusion (i.e., within 120 days of donor-derived CD19 CAR T cell infusion). The secondary endpoints are total number, incidence and severity of adverse events from 120 days to 2 years after donor-derived CD19 CAR T-cell infusion; ORR(CR+CRi) on days 45, 90, 120; duration of response(DOR), event-free survival(EFS), overall survival(OS); pharmacokinetics characteristics. The trial plan to enroll 3\~12 cases in dose escalation phase and 36 cases in dose expansion phase. Phase: PHASE1 Status: RECRUITING Conditions: B-cell Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia, in Relapse Interventions: Donor-derived CD19 CAR Therapy Bridged Allo-HSCT and Sequential Donor-derived CD22 CAR Therapy

University of Florida

A Phase I open-label, multicenter study, to evaluate the safety, feasibility, and maximum tolerated dose (MTD) of treating children with newly diagnosed DIPG or recurrent neuroblastoma with molecular targeted therapy in combination with adoptive cell therapy (Total tumor mRNA-pulsed autologous Dendritic Cells (DCs) (TTRNA-DCs), Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT) and Autologous G-CSF mobilized Hematopoietic Stem Cells (HSCs)). Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Neuroblastoma; Diffuse Intrinsic Pontine Glioma Interventions: Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT)

National Cancer Institute (NCI)

Background: CAR T-cell therapy is a promising new treatment for blood cancers. During treatment, a person s T-cells are genetically changed to kill cancer cells. Researchers want to learn more about the effects of potential problems that may be associated with this treatment. We are specifically interested in learning if and how this treatment may affect the brain or your thinking skills. Objective: To learn if CAR T-cell therapy can affect how children and adults think, process, and remember things. Eligibility: People aged 5-35 who have blood cancer that has not responded to treatment, or the blood cancer has come back after treatment, and who will receive CAR T-cell therapy. Caregivers are also needed. All participants must be able to speak and read in English or Spanish. Design: Participants will be screened with a medical history. Information from participants medical records will be collected. Participants will take tests at home or at NIH to see how well they think, read, learn, remember, reason, and pay attention. The tests will be both computerized and paper/pencil. They will take less than 1 hour to complete. Participants and a parent/adult observer will complete a 5-minute Background Information Form and a checklist of nervous system symptoms. If participants are 5 years or older, they will participate in activities to test their ability to do different thinking tasks, like answer questions, complete puzzle patterns, and remember things. Participants and their caregivers will complete questions to see if they are having specific symptoms related to receiving CAR T-cells. The questions will assess their well-being and needs. The questions will take less than 1 hour to complete. Some tests and questions will be repeated at different time points in the study. Participation will last for up to 3 years. Status: RECRUITING Conditions: Lymphoma; Leukemia

University of Florida

This is a phase I study to assess the safety and feasibility of IL-8 receptor modified patient-derived activated CD70 CAR T cell therapy in CD70+ adult glioblastoma Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Glioblastoma Multiforme; Glioblastoma Interventions: Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells

University of Florida

This study will enroll 6 DLT evaluable subjects (up to 12 patients total) where we will evaluate feasibility and safety of adoptive cellular therapy combined with IDH1/2 inhibitors in patients with recurrent or progressive oligodendroglioma WHO grade 2 and WHO grade 3. Phase: PHASE1 Status: ACTIVE_NOT_RECRUITING Conditions: Recurrent Oligodendroglioma; Progressive Oligodendroglioma Interventions: TTRNA-DC vaccines with GM-CSF; Autologous Hematopoietic Stem cells (HSCs); TTRNA-xALT; Td vaccine

TC Erciyes University

This interventional study assigns participants undergoing autologous hematopoietic stem cell transplantation to a supervised exercise program or usual care. The exercise program includes strength, endurance, and flexibility sessions for 8 weeks, 5 days per week. The control group receives usual care without a structured exercise program. Phase: NA Status: COMPLETED Conditions: Hematologic Malignacy; Autologous Hematopoietic Stem Cell Transplantation Interventions: Exercise Program

Fred Hutchinson Cancer Center

This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs, such as treosulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. rATG is used to decrease the body's immune response and may improve bone marrow function and increase blood cell counts. Adding treosulfan to a conditioning regimen with fludarabine and rATG may result in patients having less severe complications after a blood or bone marrow transplant. Phase: PHASE2 Status: COMPLETED Conditions: Bone Marrow Failure Syndrome; Congenital Amegakaryocytic Thrombocytopenia; Diamond-Blackfan Anemia; Hereditary Sideroblastic Anemia; Paroxysmal Nocturnal Hemoglobinuria; Shwachman-Diamond Syndrome; Hematologic Neoplasm With Germline GATA2 Mutation; Hematologic Neoplasm With Germline SAMD9 Mutation; Hematologic Neoplasm With Germline SAMD9L Mutation Interventions: Treosulfan; Fludarabine Phosphate; Tacrolimus; Methotrexate; Lapine T-Lymphocyte Immune Globulin; Peripheral Blood Stem Cell Transplantation; Allogeneic Bone Marrow Transplantation; Quality-of-Life Assessment; Echocardiography; Multigated Acquisition Scan; Bone Marrow Biopsy; Bone Marrow Aspiration; Biospecimen Collection; X-Ray Imaging; Computed Tomography

National Cancer Institute (NCI)

Background: People who have had an allogeneic hematopoietic stem cell transplant (HCT) have bone marrow or an immune system that is damaged. They get stem cells from a donor who is a relative. Researchers want to study stem cell donors and recipients to learn about the long-term effects of HCT. They want to learn how the stem cells change and how to improve their ability to fight cancer. Objective: To provide long-term follow-up care for people who underwent or will undergo HCT. To collect data, blood, and tissue samples to learn about late complications after HCT. Eligibility: Adults age 18 and older who will undergo HCT or underwent HCT and are surviving one year or more from the date of HCT. The stem cell donors for these recipients are also needed. Design: Recipients will have 1 visit each year. They will have a physical exam. They will answer questions about their medical history and health. They will receive screening and surveillance testing. They will complete brief questionnaires. Recipients will have blood tests. They may have tissue biopsies or specimens (such as tissue in their cheek or skin or bone marrow biopsy). Recipients will give their current address and phone number, and the same data for one or two other people, who can get in contact with them. After the first visit at the clinic, some recipients may see a doctor close to home to get the necessary information and send it to NIH. Donors will come to the clinic for 1 visit. They will answer questions about their medical history. Blood samples will be taken. Status: RECRUITING Conditions: Hematopoietic Stem Cell Transplantation; Tissue Donors

Hua Li, Chenrui Jin

Retinoblastoma (RB), which is the most common pediatric intraocular malignancy driven by RB1 inactivation, presents with clinical challenges, such as treatment toxicity, relapse, and resistance. Traditional models inadequately replicate human RB genetics or tumor heterogeneity, warranting the development of advanced in vitro platforms. Retinal organoids generated from human pluripotent or patient-specific stem cells enable three-dimensional(3D) modeling of the tumor microenvironment, drug screening, and mechanistic studies. This review summarizes RB pathogenesis, including RB1 loss, MYCN amplification, epigenetic dysregulation (e.g., METTL3-mediated m6A), and dysregulated pathways (PI3K/AKT/mTOR, Hedgehog), and highlights CRISPR-engineered organoids for identifying cone precursors as tumor origins and validating therapies (CDK4/6 inhibitors and sunitinib). Despite these advances, organoid applications are limited by high costs, variable success rates, incomplete immune/vascular mimicry, and limited scalability. Current microfluidic systems partially address vascularization but lack functional perfusion. Future efforts should integrate multiomics, refine vascularization via 3D bioprinting, and develop immunocompetent models to address the disparity between preclinical research and clinical application. Organoid technology has the potential to advance personalized therapies and ultimately enhance the survival and quality of life of patients with RB worldwide.

Birte Doludda, Warsha Barde, Francesco D'Egidio et al.

The 38 currently registered clinical trials with the keyword "adult neurogenesis" indicate growing interest in new neurons as a target for intervention. Today, we have strong evidence that adult neurogenesis is involved in hippocampal function and can contribute to brain functions in health and disease. Neurogenesis research can now ask new questions, such as (1) the identity of stem cells and their input integration for initiating neurogenesis, (2) the nature of the neurogenic niche and neurogenesis without stem cell activity, (3) the complex functionality beyond the hippocampus, and (4) evolutionary and computational theory, including neurogenic neural networks for artificial intelligence.

Shinya Yamanaka

Twenty years have passed since the first demonstration of mouse induced pluripotent stem cells (iPSCs). What began as an unexpected observation in Kyoto quickly transformed stem cell biology and regenerative medicine worldwide. Over the past two decades, we have gained profound insights into the molecular mechanisms underlying cellular reprogramming and pluripotency. The technology has continued to evolve-becoming safer, more efficient, and more versatile. Today, iPSCs serve as a foundation for wide-ranging applications, from disease modeling and drug discovery to regenerative therapies and rejuvenation research. In this review, I reflect on the scientific journey of iPSCs, highlight key milestones in our understanding of reprogramming, and discuss the expanding clinical and societal impact of iPSCs.

Mahtab Avijgan, Amal Nazaraliyev, Klas Blomgren et al.

Postnatal skeletal growth in childhood and adolescence depends on cartilage organs called (epiphyseal) growth plates. Studies in the last decade have identified populations of skeletal stem cells within mouse growth plates' resting zones. While cellular quiescence is vital for the maintenance of many tissue-resident stem cell populations, the resting zone chondrocytes have been labelled "quiescent" for decades. However, the features of cellular quiescence that have been reported in the postnatal resting zone, how they were defined or experimentally assessed, and knowledge gaps relative to other quiescent cell types, remain to be well described. To address this, we conducted a systematic review, using the PRISMA guidelines, to identify studies of resting zone chondrocytes including the prefix "quiescen*". Definitions, keywords, chronological data and experimental findings were extracted. Our analysis demonstrated that, compared to those in other well-studied tissues, features of cellular quiescence in RZ chondrocytes remain poorly reported and underexplored, with limited molecular and functional characterization. Furthermore, while most identified studies reported changes in cell division parameters, integration between cues controlling resting zone cell quiescence is incomplete and heterogeneity among the various sub-populations of RZ cells/potential quiescent states is yet to be fully determined. This review identifies consensuses and knowledge gaps between studies and between quiescent RZ cells and those in other tissues and can act to enhance consistency and comparability in future studies of "quiescence" in the RZ chondrocytes.

Oxford researchers found that while AI models like GPT-4 correctly diagnose medical conditions 94.9% of the time in isolation, real people using the same AI achieve less than 34.5% accuracy—no better than Google. The failure point isn't the AI's knowledge but the conversation itself, revealing a critical flaw in how medical chatbots are currently deployed.

Researchers discovered that the H3K27M mutation in deadly childhood brain tumors drives excessive lactate production, which directly activates DNA synthesis machinery through lactylation of the enzyme NME1. This finding enabled development of a deuterium-based MRI technique that can visualize tumor metabolism at clinical field strength and detect treatment response early—potentially transforming how we monitor these aggressive cancers.

Researchers tracked 34 cutaneous T-cell lymphoma patients using comprehensive multi-omics and serial sampling, creating the first single-cell resolution map of how cancer evolves to escape treatment. The study identified specific recurrent mutations — including STAT3 D661Y driving HDAC inhibitor resistance and EZH2 alterations targetable with existing drugs — providing a roadmap for genome-guided therapeutic decisions and improved disease monitoring.